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Gao Y, De S, Brazil DP. The Role of GREMLIN1, a Bone Morphogenetic Protein Antagonist, in Cancer Stem Cell Regulation. Cells 2025; 14:578. [PMID: 40277903 PMCID: PMC12025430 DOI: 10.3390/cells14080578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/02/2025] [Accepted: 04/07/2025] [Indexed: 04/26/2025] Open
Abstract
Cancer remains a leading cause of death globally, characterized by uncontrolled cell proliferation, tumor growth and metastasis. Bone morphogenetic proteins (BMPs) and their growth differentiation factor (GDF) relatives are crucial regulators of developmental processes such as limb, kidney and lung formation, cell fate determination, cell proliferation, and apoptosis. Cancer stem cells (CSCs) are a subpopulation of self-renewing cells within tumors that possess stemness properties and a tumor cell-forming capability. The presence of CSCs in a tumor is linked to growth, metastasis, treatment resistance and cancer recurrence. The tumor microenvironment in which CSCs exist also plays a critical role in the onset, progression and treatment resistance in many cancers. Growth factors such as BMPs and GDFs counterbalance transforming growth factor-beta (TGF-β) in the maintenance of CSC pluripotency and cancer cell differentiation. BMP signaling typically functions in a tumor suppressor role in various cancers by inducing CSC differentiation and suppressing stemness characteristics. This differentiation process is vital, as it curtails the self-renewal capacity that characterizes CSCs, thereby limiting their ability to sustain tumor growth. The interplay between BMPs and their secreted antagonists, such as GREM1, Noggin and Chordin, adds another layer of complexity to CSC regulation. Human cancers such as gastric, colorectal, glioblastoma, and breast cancer are characterized by GREMLIN1 (GREM1) overexpression, leading to inhibition of BMP signaling, facilitating the maintenance of pluripotency in CSCs, thus promoting tumorigenesis. GREM1 overexpression may also contribute to CSC immune evasion, further exacerbating patient prognoses. In addition to BMP inhibition, GREM1 has been implicated as a target of fibroblast growth factor (FGF) → Sonic hedgehog (Shh) signaling, as well as the Wnt/Frizzled pathway, both of which may contribute to the maintenance of CSC stemness. The complex role of BMPs and their antagonists in regulating CSC behavior underscores the importance of a balanced BMP signaling pathway. This article will summarize current knowledge of BMP and GREM1 regulation of CSC function, as well as conflicting data on the exact role of GREM1 in modulating CSC biology, tumor formation and cancer. Targeting this pathway by inhibiting GREM1 using neutralizing antibodies or small molecules may hold early-stage promise for novel therapeutic strategies aimed at reducing CSC burden in cancers and improving patient outcomes.
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Affiliation(s)
| | | | - Derek P. Brazil
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK; (Y.G.); (S.D.)
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2
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Wang J, Xu P, Ji Z, Cheng C, Liu Y, Du G, Zhang S, Miao J, Wang D, Chen R, Li D, Zhang K, Zhao H, Sun Y, Chen X, Jing N, Liu K, He Y, Xi X, Zhang Y, Wang N, Xu L, Yao J, Gao X, Zhou J, Fan S, Wang X, Dong S, Chen F, Hou J, Zhang M, Gao WQ, Shen L, Zhang P, Zhu HH. A Gremlin 1-expressing splenic niche cell population restrains chronic myeloid leukemia by antagonizing the BMP pathway. NATURE CANCER 2025; 6:666-681. [PMID: 40097655 DOI: 10.1038/s43018-025-00933-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 02/17/2025] [Indexed: 03/19/2025]
Abstract
The spleen plays a critical role in the pathogenesis of leukemia. However, our understanding of the splenic niche is very limited. Herein, we report that induced expression of the secreted protein Gremlin 1 in a mouse model restrains chronic myeloid leukemia (CML) progression and synergizes with tyrosine kinase inhibitor treatment, whereas blockade of Gremlin 1 promotes CML development. Intriguingly, the effect of Gremlin 1 is most evident in the spleen but not in the bone marrow. Gremlin 1 induces apoptosis of leukemic stem cells via antagonizing the BMP pathway. Single-cell RNA sequencing and experimental validation together show that Gremlin 1 marks a unique stromal cell population in the spleens of both mice and humans. Genetic ablation of Gremlin 1+ cells leads to accelerated CML progression. Collectively, Gremlin 1 and Gremlin 1+ cells are key defensive niche components in the spleen that limit CML progression, revealing an unprecedented mechanism for the body to fight off leukemia.
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MESH Headings
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Animals
- Spleen/metabolism
- Spleen/pathology
- Mice
- Humans
- Signal Transduction
- Bone Morphogenetic Proteins/metabolism
- Bone Morphogenetic Proteins/antagonists & inhibitors
- Intercellular Signaling Peptides and Proteins/metabolism
- Intercellular Signaling Peptides and Proteins/genetics
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Disease Models, Animal
- Apoptosis
- Disease Progression
- Mice, Inbred C57BL
- Stem Cell Niche
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Affiliation(s)
- Jinming Wang
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Penghui Xu
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Zhongzhong Ji
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Chaping Cheng
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yiyun Liu
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Genyu Du
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Shilei Zhang
- Department of Pathology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Juju Miao
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Deng Wang
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Ruoyang Chen
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dawei Li
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kai Zhang
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Huifang Zhao
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yujiao Sun
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xinyu Chen
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Na Jing
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Kaiyuan Liu
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yuman He
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xialian Xi
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yingchao Zhang
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Nan Wang
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Longmei Xu
- Shanghai Cancer Institute, Shanghai, China
| | - Jufang Yao
- Animal Facility of Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaomei Gao
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Jianhua Zhou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Songqing Fan
- Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiaorui Wang
- Clinical Laboratory Medicine Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuxian Dong
- Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fangli Chen
- Department of Hematology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian Hou
- Department of Hematology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming Zhang
- Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei-Qiang Gao
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Lijing Shen
- Department of Hematology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Pengcheng Zhang
- School of Biomedical Engineering, ShanghaiTech University, Shanghai, China
| | - Helen He Zhu
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
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3
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Handschin C, Shalhoub H, Mazet A, Guyon C, Dusserre N, Boutet-Robinet E, Oliveira H, Guillermet-Guibert J. Biotechnological advances in 3D modeling of cancer initiation. Examples from pancreatic cancer research and beyond. Biofabrication 2025; 17:022008. [PMID: 40018875 DOI: 10.1088/1758-5090/adb51c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 02/12/2025] [Indexed: 03/01/2025]
Abstract
In recent years, biofabrication technologies have garnered significant attention within the scientific community for their potential to create advancedin vitrocancer models. While these technologies have been predominantly applied to model advanced stages of cancer, there exists a pressing need to develop pertinent, reproducible, and sensitive 3D models that mimic cancer initiation lesions within their native tissue microenvironment. Such models hold profound relevance for comprehending the intricacies of cancer initiation, to devise novel strategies for early intervention, and/or to conduct sophisticated toxicology assessments of putative carcinogens. Here, we will explain the pivotal factors that must be faithfully recapitulated when constructing these models, with a specific focus on early pancreatic cancer lesions. By synthesizing the current state of research in this field, we will provide insights into recent advances and breakthroughs. Additionally, we will delineate the key technological and biological challenges that necessitate resolution in future endeavors, thereby paving the way for more accurate and insightfulin vitrocancer initiation models.
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Affiliation(s)
- C Handschin
- Université de Bordeaux, Tissue Bioengineering - BioTis, INSERM U1026, Bordeaux, F-33000, France
- INSERM U1026, ART BioPrint, F-33000 Bordeaux, France
| | - H Shalhoub
- CRCT, Université de Toulouse, Inserm, CNRS, Centre de Recherches en Cancérologie de Toulouse, 2 av Hubert Curien, Toulouse, France
- Labex Toucan, 2 av Hubert Curien, Toulouse, France
| | - A Mazet
- Université de Bordeaux, Tissue Bioengineering - BioTis, INSERM U1026, Bordeaux, F-33000, France
- INSERM U1026, ART BioPrint, F-33000 Bordeaux, France
| | - C Guyon
- CRCT, Université de Toulouse, Inserm, CNRS, Centre de Recherches en Cancérologie de Toulouse, 2 av Hubert Curien, Toulouse, France
- Labex Toucan, 2 av Hubert Curien, Toulouse, France
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UT3, Toulouse, France
| | - N Dusserre
- Université de Bordeaux, Tissue Bioengineering - BioTis, INSERM U1026, Bordeaux, F-33000, France
- INSERM U1026, ART BioPrint, F-33000 Bordeaux, France
| | - E Boutet-Robinet
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UT3, Toulouse, France
| | - H Oliveira
- Université de Bordeaux, Tissue Bioengineering - BioTis, INSERM U1026, Bordeaux, F-33000, France
- INSERM U1026, ART BioPrint, F-33000 Bordeaux, France
| | - J Guillermet-Guibert
- CRCT, Université de Toulouse, Inserm, CNRS, Centre de Recherches en Cancérologie de Toulouse, 2 av Hubert Curien, Toulouse, France
- Labex Toucan, 2 av Hubert Curien, Toulouse, France
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UT3, Toulouse, France
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4
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Li H, Zhou Y, Xiao J, Liu F. A comprehensive prognostic and immunological implications of Gremlin 1 in lung adenocarcinoma. Front Immunol 2025; 16:1529195. [PMID: 40066442 PMCID: PMC11891240 DOI: 10.3389/fimmu.2025.1529195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Accepted: 02/04/2025] [Indexed: 03/15/2025] Open
Abstract
Background Lung adenocarcinoma (LUAD) is a prevalent form of lung cancer globally, known for its high invasiveness, metastatic potential, and notable heterogeneity, particularly in its response to immunotherapy. Gremlin 1 (GREM1) is implicated in tumor progression and poor prognosis in multiple cancers. However, GREM1's specific role in LUAD remains unclear. This study systematically examines GREM1 expression in LUAD and its association with tumor progression, immune microenvironment, and prognosis. Methods Gene expression data from the TCGA and GSE31210 databases were analyzed using Weighted Gene Co-expression Network Analysis (WGCNA), GO and KEGG enrichment analyses. The prognostic value of GREM1 was evaluated through survival analysis, Cox regression, and Kaplan-Meier curves. Additionally, immune microenvironment analysis was conducted to explore the relationship between GREM1 and immune cell infiltration. In vitro experiments, including Western blot and assays for cell proliferation, migration, and invasion, were performed to confirm the specific role of GREM1 in LUAD cells. Results GREM1 was significantly upregulated in tumor tissues and correlated with poor prognosis. Moreover, GREM1 was significantly associated with immune cell infiltration and immunotherapy response within the immune microenvironment. In vitro experiments confirmed that GREM1 overexpression significantly promoted LUAD cell proliferation, migration, and epithelial-mesenchymal transition (EMT), whereas GREM1 knockdown suppressed these functions. Conclusions A comprehensive analysis indicates that GREM1 is crucial in LUAD progression, with its overexpression predicting poor prognosis. GREM1 could be a potential therapeutic target for LUAD, providing insights for personalized therapy optimization.
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Affiliation(s)
- Hongyan Li
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yang Zhou
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jiaqing Xiao
- Institute of Disinfection and Infection Control, Heilongjiang Provincial Center for Disease Control and Prevention, Harbin, China
| | - Fang Liu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
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Ye C, Xia L, Gong R, Chang J, Sun Q, Xu J, Li F. Integrating plasma proteome with genome reveals novel protein biomarkers in colorectal cancer. Clin Transl Oncol 2025; 27:567-579. [PMID: 39017955 DOI: 10.1007/s12094-024-03616-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 07/09/2024] [Indexed: 07/18/2024]
Abstract
BACKGROUND Biomarkers for colorectal cancer (CRC) can complement population screening methods, but so far, few plasma proteins have been identified as biomarkers for CRC. This study aims to identify potential protein biomarkers and therapeutic targets for CRC within the proteome range. METHODS We extracted summary-level data of circulating protein from 7 published genome-wide association studies (GWASs) of plasma proteome for Mendelian randomization (MR), summary-data-based MR (SMR), and co-localization analyses to screen and validate proteins with causal effects in CRC. In addition, we further conducted druggability evaluation, prognosis analysis at the transcriptional level, and enrichment expression at the single-cell level, highlighting the important role of these plasma protein biomarkers in CRC. RESULTS We identified 117 plasma protein biomarkers associated with CRC risk, with 9 proteins showing stronger genetic correlations in Bayesian co-localization (PP.H4 > 0.70). Further, we found 26 protein-coding genes already used in targeted drug development and may potentially become therapeutic targets for CRC. In prognosis analysis, the encoding genes of plasma proteins exhibited consistent effects with MR analysis and can serve as prognostic biomarkers for CRC. Additionally, we also found that the differentially expressed proteins are mainly expressed in fibroblasts, endothelial cells, macrophages, and T cells. CONCLUSION Our study has identified plasma protein biomarkers associated with CRC risk, which may complement population screening methods for CRC and achieve more precise treatment for patients.
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Affiliation(s)
- Changchun Ye
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Leizhou Xia
- Department of General Surgery, Affiliated People's Hospital, Jiangsu University, Zhenjiang, China
| | - Ruimin Gong
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jingbo Chang
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qi Sun
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jiaxi Xu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University Health Science Center, Xi'an, China.
| | - Fanni Li
- Department of Talent Highland, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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Good HJ, Larsen F, Shin AE, Zhang L, Derouet M, Meriwether D, Worthley D, Reddy ST, Wang TC, Asfaha S. Prostaglandin E 2 and Akt Promote Stemness in Apc Mutant Dclk1+ Cells to Give Rise to Colitis-associated Cancer. Cell Mol Gastroenterol Hepatol 2025; 19:101469. [PMID: 39884575 PMCID: PMC11999635 DOI: 10.1016/j.jcmgh.2025.101469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 01/22/2025] [Accepted: 01/22/2025] [Indexed: 02/01/2025]
Abstract
BACKGROUND & AIMS Loss of the tumor suppressor gene Apc in Lgr5+ intestinal stem cells results in aberrant Wnt signaling and colonic tumorigenesis. In the setting of injury, however, we and others have also shown that non-stem cells can give rise to colonic tumors. The mechanism by which inflammation leads to cellular plasticity and cancer, however, remains largely unknown. METHODS RNA expression analysis of Wnt, COX, and Akt signaling was assessed in patients with quiescent or active ulcerative colitis (UC) and patients with UC-associated neoplasia using available datasets. The role of COX signaling in colonic tumorigenesis was examined using epithelial and doublecortin-like kinase 1 (Dclk1)+ cell-specific conditional COX-1 knockout mice and pharmacologic treatment with different nonsteroidal anti-inflammatory drugs. RESULTS In this study, we show that prostaglandins and phospho-Akt are key inflammatory mediators that promote stemness in Apc mutant Dclk1+ cells that give rise to colorectal cancer. Moreover, prostaglandin E2 (PGE2) and Akt are increased in colitis in both mice and humans, leading to inflammation-associated dysplasia upon activation of Wnt signaling. Importantly, inhibition of epithelial-derived COX-1 by aspirin or conditional knockout in Dclk1+ cells reduced PGE2 levels and prevented the development of inflammation-associated colorectal cancer. CONCLUSIONS Our data shows that epithelial and Dclk1+ cell-derived COX-1 plays an important role in inflammation-associated tumorigenesis. Importantly, low-dose aspirin was effective in chemo-prevention through inhibition of COX-1 that reduced colitis-associated cancer.
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Affiliation(s)
- Hayley J Good
- Department of Medicine, University of Western Ontario, London, Ontario, Canada; Verspeeten Family Cancer Centre, London Health Sciences Centre, London, Ontario, Canada
| | - Frederikke Larsen
- Department of Medicine, University of Western Ontario, London, Ontario, Canada; Verspeeten Family Cancer Centre, London Health Sciences Centre, London, Ontario, Canada
| | - Alice E Shin
- Department of Medicine, University of Western Ontario, London, Ontario, Canada; Verspeeten Family Cancer Centre, London Health Sciences Centre, London, Ontario, Canada
| | - Liyue Zhang
- Department of Medicine, University of Western Ontario, London, Ontario, Canada; Verspeeten Family Cancer Centre, London Health Sciences Centre, London, Ontario, Canada
| | - Mathieu Derouet
- Department of Medicine, University of Western Ontario, London, Ontario, Canada; Verspeeten Family Cancer Centre, London Health Sciences Centre, London, Ontario, Canada
| | - David Meriwether
- Department of Medicine, Division of Cardiology, UCLA David Geffen School of Medicine, Los Angeles, California
| | - Daniel Worthley
- South Australian Health Medical Research Institute, North Terrace Adelaide, Australia
| | - Srinivasa T Reddy
- Department of Medicine, Division of Cardiology, UCLA David Geffen School of Medicine, Los Angeles, California
| | - Timothy C Wang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York
| | - Samuel Asfaha
- Department of Medicine, University of Western Ontario, London, Ontario, Canada; Verspeeten Family Cancer Centre, London Health Sciences Centre, London, Ontario, Canada.
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Pellon-Cardenas O, Rout P, Hassan S, Fokas E, Ping H, Patel I, Patel J, Plotsker O, Wu A, Kumar R, Akther M, Logerfo A, Wu S, Wagner DE, Boffelli D, Walton KD, Manieri E, Tong K, Spence JR, Bessman NJ, Shivdasani RA, Verzi MP. Dynamic Reprogramming of Stromal Pdgfra-expressing cells during WNT-Mediated Transformation of the Intestinal Epithelium. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.22.634326. [PMID: 39896606 PMCID: PMC11785226 DOI: 10.1101/2025.01.22.634326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Stromal fibroblasts regulate critical signaling gradients along the intestinal crypt-villus axis1 and provide a niche that supports adjacent epithelial stem cells. Here we report that Pdgfra-expressing fibroblasts secrete ligands that promote a regenerative-like state in the intestinal mucosa during early WNT-mediated tumorigenesis. Using a mouse model of WNT-driven oncogenesis and single-cell RNA sequencing (RNA-seq) of mesenchyme cell populations, we revealed a dynamic reprogramming of Pdgfra+ fibroblasts that facilitates WNT-mediated tissue transformation. Functional assays of potential mediators of cell-to-cell communication between these fibroblasts and the oncogenic epithelium revealed that TGFB signaling is notably induced in Pdgfra+ fibroblasts in the presence of oncogenic epithelium, and TGFB was essential to sustain regenerative-like growth of organoids ex vivo. Genetic reduction of Cdx2 in the β-catenin mutant epithelium elevated the fetal-like/regenerative transcriptome and accelerated WNT-dependent onset of oncogenic transformation of the tissue in vivo. These results demonstrate that Pdgfra+ fibroblasts are activated during WNT-driven oncogenesis to promote a regenerative state in the epithelium that precedes and facilitates formation of tumors.
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Affiliation(s)
| | - P Rout
- Department of Genetics, Rutgers University, Piscataway, NJ, USA
| | - S Hassan
- Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA
| | - E Fokas
- Department of Genetics, Rutgers University, Piscataway, NJ, USA
| | - He Ping
- Department of Genetics, Rutgers University, Piscataway, NJ, USA
| | - I Patel
- Department of Genetics, Rutgers University, Piscataway, NJ, USA
| | - J Patel
- Department of Genetics, Rutgers University, Piscataway, NJ, USA
| | - O Plotsker
- Department of Genetics, Rutgers University, Piscataway, NJ, USA
| | - A Wu
- Department of Genetics, Rutgers University, Piscataway, NJ, USA
| | - R Kumar
- Department of Genetics, Rutgers University, Piscataway, NJ, USA
| | - M Akther
- Department of Genetics, Rutgers University, Piscataway, NJ, USA
| | - A Logerfo
- Department of Genetics, Rutgers University, Piscataway, NJ, USA
| | - S Wu
- Department of Genetics, Rutgers University, Piscataway, NJ, USA
| | - D E Wagner
- Department of Obstetrics, University of California, San Francisco, San Francisco, CA, USA
| | - D Boffelli
- Department of Pediatrics, Cedars-Sinai Guerin Children's, Los Angeles, CA, USA
| | - K D Walton
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - E Manieri
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - K Tong
- Department of Medical Sciences, Hackensack Meridian Health School of Medicine, Nutley, NJ, USA
| | - J R Spence
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - N J Bessman
- Department of Medicine, New Jersey Medical School, Rutgers, Newark, NJ, USA
| | - R A Shivdasani
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - M P Verzi
- Department of Genetics, Rutgers University, Piscataway, NJ, USA
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick NJ, USA
- Human Genetics Institute of New Jersey, Rutgers University, New Brunswick NJ, USA
- Lead contact
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8
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Shay JES, Yilmaz ÖH. Dietary and metabolic effects on intestinal stem cells in health and disease. Nat Rev Gastroenterol Hepatol 2025; 22:23-38. [PMID: 39358589 DOI: 10.1038/s41575-024-00980-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/05/2024] [Indexed: 10/04/2024]
Abstract
Diet and nutritional metabolites exhibit wide-ranging effects on health and disease partly by altering tissue composition and function. With rapidly rising rates of obesity, there is particular interest in how obesogenic diets influence tissue homeostasis and risk of tumorigenesis; epidemiologically, these diets have a positive correlation with various cancers, including colorectal cancer. The gastrointestinal tract is a highly specialized, continuously renewing tissue with a fundamental role in nutrient uptake and is, in turn, influenced by diet composition and host metabolic state. Intestinal stem cells are found at the base of the intestinal crypt and can generate all mature lineages that comprise the intestinal epithelium and are uniquely influenced by host diet, metabolic by-products and energy dynamics. Similarly, tumour growth and metabolism can also be shaped by nutrient availability and host diet. In this Review, we discuss how different diets and metabolic changes influence intestinal stem cells in homeostatic and pathological conditions, as well as tumorigenesis. We also discuss how dietary changes and composition affect the intestinal epithelium and its surrounding microenvironment.
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Affiliation(s)
- Jessica E S Shay
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Ömer H Yilmaz
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA.
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
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9
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Zhu M, Zhou H, Zhuo Y, Liu C, Li J, He P, Liu N, Zhao Z, Huafeng P. Pan-cancer multi-omics analysis to identify the potential pro-oncogenic properties of GREM1 as a promising targets for cancer prognosis and therapeutics. Int J Immunopathol Pharmacol 2025; 39:3946320251331850. [PMID: 40231657 PMCID: PMC12033649 DOI: 10.1177/03946320251331850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 03/16/2025] [Indexed: 04/16/2025] Open
Abstract
We aimed to investigate the potential pro-oncogenic properties of GREM1 by Pan-cancer multi-omics analysis. Accumulating evidence has highlighted that GREM1 (Gremlin 1), serves as an inhibitor of BMP (Bone Morphogenetic Protein) family, involve in bone related diseases, carcinogenesis, cell stemness, and cell differentiation. However, the effect and underlying mechanism of GREM1 on the cancer biology remain largely elusive. The mRNA expression of GREM1 were extracted from GTEx (Genotype-Tissue Expression) and TCGA (The Cancer Genome Atlas) database. Analysis of OS (Overall Survival), PFI (Progression Free Interval), DSS (Disease-Specific Survival), and ROC (Receiver Operating Characteristic) were performed to predicted prognostic value of GREM1 in various cancers. The TIMER (Tumor Immune Estimation Resource) online tool was used to investigate the relationship between GREM1 transcriptional level and infiltration of immune cells. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis and GO (Gene Ontology) analysis were used to investigate the GREM1 related molecular events, and then constructed a PPI (Protein-Protein Interaction) network via the STRING (Search Tool for the Retrieval of Interaction Genes/Proteins) online tool. Western blot was performed to investigate the indicated protein expression. In the present study, our results showed that GREM1 tended to be upregulated in various cancers, which would correlate with the poor prognosis. Mechanistically, our results showed that GREM1 involve in regulating the ECM-receptor interaction pathway, upregulation of MMP activity, angiogenesis, and immune cell infiltration. In vitro studies, our results further showed that BMP agonist significantly decreased the protein level of GREM1 in GES-1 cells and BGC cells, which accompanied by inhibiting migration and proliferation in GES-1 cells and BGC cells. BMP inhibitor significantly promoted GREM1 expression and migration in BGC cells, but not GES-1 cells. GREM1 might serve as a potential and promising prognostic biomarker for drug development and cancer treatment.
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Affiliation(s)
- Menglu Zhu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hengli Zhou
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yue Zhuo
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Changhua Liu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiaxin Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Peiyao He
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Naihua Liu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ziming Zhao
- Guangdong Province Engineering Technology Research Institute of T.C.M, Guangzhou, China
| | - Pan Huafeng
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, China
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10
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Ke BJ, Dragoni G, Matteoli G. Fibroblast Heterogeneity in Inflammatory Bowel Disease. Int J Mol Sci 2024; 25:13008. [PMID: 39684719 DOI: 10.3390/ijms252313008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 10/15/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
Intestinal fibroblasts are pivotal players in maintaining tissue homeostasis and orchestrating responses to injury and inflammation within the gastrointestinal (GI) tract. Fibroblasts contribute significantly to the pathogenesis of inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis (UC), by secreting pro-inflammatory cytokines, modulating immune cell activity, and promoting fibrosis. In addition, fibroblasts play crucial roles in tissue repair and regeneration following acute injury or chronic inflammation. The dysregulation of fibroblast functions can lead to fibrotic complications, such as intestinal strictures and obstruction, which are common in advanced stages of IBD. Understanding the complex interplay between fibroblasts and other cell types in the intestine is essential to elucidate the underlying mechanisms of intestinal diseases and identify novel therapeutic targets. Future research aimed at deciphering the heterogeneity of intestinal fibroblasts and their dynamic roles in disease progression holds promise for the development of precision therapies to mitigate fibrosis and inflammation in intestinal disorders.
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Affiliation(s)
- Bo-Jun Ke
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium
| | - Gabriele Dragoni
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Gianluca Matteoli
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, 3000 Leuven, Belgium
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11
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Jin Z, Cao Y. Gremlin1: a BMP antagonist with therapeutic potential in Oncology. Invest New Drugs 2024; 42:716-727. [PMID: 39347850 DOI: 10.1007/s10637-024-01474-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 09/18/2024] [Indexed: 10/01/2024]
Abstract
Gremlins, originating from early 20th-century Western folklore, are mythical creatures known for causing mechanical malfunctions and electronic failures, aptly dubbed "little devils". Analogously, GREM1 acts like a horde of these mischievous entities by antagonizing the bone morphogenetic protein (BMP signaling) pathway or through other non-BMP dependent mechanisms (such as binding to Fibroblast Growth Factor Receptor 1and Epidermal Growth Factor Receptor) contributing to the malignant progression of various cancers. The overexpression of GREM1 promotes tumor cell growth and survival, enhances angiogenesis within the tumor microenvironment, and creates favorable conditions for tumor development and dissemination. Consequently, inhibiting the activity of GREM1 or blocking its interaction with BMP presents a promising strategy for suppressing tumor growth and metastasis. However, the role of GREM1 in cancer remains a subject of debate, with evidence suggesting both oncogenic and tumor-suppressive functions. Currently, several pharmaceutical companies are researching the GREM1 target, with some advancing to Phase I/II clinical trials. This article will provide a detailed overview of the GREM1 target and explore its potential role in cancer therapy.
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Affiliation(s)
- Zhao Jin
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Yanshuo Cao
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
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12
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Liu S, Ren J, Hu Y, Zhou F, Zhang L. TGFβ family signaling in human stem cell self-renewal and differentiation. CELL REGENERATION (LONDON, ENGLAND) 2024; 13:26. [PMID: 39604763 PMCID: PMC11602941 DOI: 10.1186/s13619-024-00207-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/16/2024] [Accepted: 11/01/2024] [Indexed: 11/29/2024]
Abstract
Human stem cells are undifferentiated cells with the capacity for self-renewal and differentiation into distinct cell lineages, playing important role in the development and maintenance of diverse tissues and organs. The microenvironment of stem cell provides crucial factors and components that exert significant influence over the determination of cell fate. Among these factors, cytokines from the transforming growth factor β (TGFβ) superfamily, including TGFβ, bone morphogenic protein (BMP), Activin and Nodal, have been identified as important regulators governing stem cell maintenance and differentiation. In this review, we present a comprehensive overview of the pivotal roles played by TGFβ superfamily signaling in governing human embryonic stem cells, somatic stem cells, induced pluripotent stem cells, and cancer stem cells. Furthermore, we summarize the latest research and advancements of TGFβ family in various cancer stem cells and stem cell-based therapy, discussing their potential clinical applications in cancer therapy and regeneration medicine.
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Affiliation(s)
- Sijia Liu
- International Biomed-X Research Center, Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiang Ren
- The First Affiliated Hospital, MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Institute of Biomedical Innovation, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yanmei Hu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Fangfang Zhou
- The First Affiliated Hospital, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Long Zhang
- International Biomed-X Research Center, Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
- The First Affiliated Hospital, MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Institute of Biomedical Innovation, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China.
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China.
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13
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Jiang Y, Fu Z, Chen Y, Jin Q, Yang Y, Lin Z, Li C, Gao Y, Dong Z, He Y, Mao X, He Y, Zhang Q, Zhang Q, Li N. Mapping and tracing Grem1 + stromal cells in an Apc Min/+ mouse utilizing cryopreserved intestinal sections prepared via modified Swiss-roll technique. iScience 2024; 27:111173. [PMID: 39563897 PMCID: PMC11574797 DOI: 10.1016/j.isci.2024.111173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 06/18/2024] [Accepted: 10/10/2024] [Indexed: 11/21/2024] Open
Abstract
Grem1+ cancer-associated fibroblasts (CAFs) are crucial in colorectal cancer (CRC) development, yet technical challenges have limited understanding of their origins, spatiotemporal distribution, and potential roles. Here, we devised a custom mold, optimizing the gut Swiss-roll technique to create a single cryopreserved slide for comprehensive staining. Our integrated approach uncovered a marked increase in Grem1+ CAFs within Apc Min/+ mouse tumors at 12 weeks, compared to normal mucosa. Subsequent lineage tracing in Grem1-CreER T2 ; R26-LSL-tdTomato; Apc Min/+ mice revealed that most Grem1+ CAFs infiltrating the tumor core originated from Grem1+ intestinal reticular stem cells (iRSCs). A minor subset of Grem1+ CAFs, located in the submucosa, retained characteristics of Grem1+ intestinal sub-epithelial myofibroblasts (ISEMFs). Altogether, CAFs derived from Grem1+ iRSCs may serve as a principal stromal cell type driving early-stage CRC progression, while Grem1+ ISEMFs contribute less from a more distant location. Hence, targeting Grem1+ CAFs presents an early and promising therapeutic strategy in CRC.
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Affiliation(s)
- Youheng Jiang
- Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
| | - Zhang Fu
- Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
- Department of Geriatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, China
| | - Yanfang Chen
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
| | - Qunlong Jin
- Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
| | - Yanming Yang
- Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
| | - Zerong Lin
- Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
| | - Changxue Li
- Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
| | - Yunfei Gao
- Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
- Department of Otolaryngology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
| | - Zepeng Dong
- Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
| | - Yang He
- School of Mechanical Engineering and Automation, Harbin Institute of Technology, Shenzhen 518107, China
| | - Xinjun Mao
- Department of Anesthesiology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Yulong He
- Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
| | - Qingyuan Zhang
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
| | - Qi Zhang
- Department of Anesthesiology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
| | - Ningning Li
- Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
- China-UK Institute for Frontier Science, Shenzhen 518107, China
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Chen SM, Guo BJ, Feng AQ, Wang XL, Zhang SL, Miao CY. Pathways regulating intestinal stem cells and potential therapeutic targets for radiation enteropathy. MOLECULAR BIOMEDICINE 2024; 5:46. [PMID: 39388072 PMCID: PMC11467144 DOI: 10.1186/s43556-024-00211-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 09/19/2024] [Indexed: 10/12/2024] Open
Abstract
Radiotherapy is a pivotal intervention for cancer patients, significantly impacting their treatment outcomes and survival prospects. Nevertheless, in the course of treating those with abdominal, pelvic, or retroperitoneal malignant tumors, the procedure inadvertently exposes adjacent intestinal tissues to radiation, posing risks of radiation-induced enteropathy upon reaching threshold doses. Stem cells within the intestinal crypts, through their controlled proliferation and differentiation, support the critical functions of the intestinal epithelium, ensuring efficient nutrient absorption while upholding its protective barrier properties. Intestinal stem cells (ISCs) regulation is intricately orchestrated by diverse signaling pathways, among which are the WNT, BMP, NOTCH, EGF, Hippo, Hedgehog and NF-κB, each contributing to the complex control of these cells' behavior. Complementing these pathways are additional regulators such as nutrient metabolic states, and the intestinal microbiota, all of which contribute to the fine-tuning of ISCs behavior in the intestinal crypts. It is the harmonious interplay among these signaling cascades and modulating elements that preserves the homeostasis of intestinal epithelial cells (IECs), thereby ensuring the gut's overall health and function. This review delves into the molecular underpinnings of how stem cells respond in the context of radiation enteropathy, aiming to illuminate potential biological targets for therapeutic intervention. Furthermore, we have compiled a summary of several current treatment methodologies. By unraveling these mechanisms and treatment methods, we aspire to furnish a roadmap for the development of novel therapeutics, advancing our capabilities in mitigating radiation-induced intestinal damage.
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Affiliation(s)
- Si-Min Chen
- Department of Pharmacology, Second Military Medical University/Naval Medical University, 325 Guo He Road, Shanghai, 200433, China
| | - Bing-Jie Guo
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - An-Qiang Feng
- Department of Digestive Disease, Xuzhou Central Hospital, Xuzhou, China
| | - Xue-Lian Wang
- School of Medicine, Shanghai University, Shanghai, China
| | - Sai-Long Zhang
- Department of Pharmacology, Second Military Medical University/Naval Medical University, 325 Guo He Road, Shanghai, 200433, China.
| | - Chao-Yu Miao
- Department of Pharmacology, Second Military Medical University/Naval Medical University, 325 Guo He Road, Shanghai, 200433, China.
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Yu Q, Xu S, Weng S, Ye L, Zheng H, Li D. GREM1 may be a biological indicator and potential target of bladder cancer. Sci Rep 2024; 14:23280. [PMID: 39375386 PMCID: PMC11458565 DOI: 10.1038/s41598-024-73655-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 09/19/2024] [Indexed: 10/09/2024] Open
Abstract
Gremlin 1 (GREM1) can regulate the development of many cancers. However, a few studies have revealed the role of GREM1 in bladder cancer (BC). To evaluate the expression and potential function of GREM1 in bladder cancer, we used R version 3.6.3 and related packages to analyze the data from common databases. Samples from our institution were assessed by immunohistochemical staining (IHC), which was approved by the Institutional Ethics Committee (K20220830). GREM1 was highly expressed in BC tissues according to the TCGA and IHC data. Data from TCGA, GSE31684, GSE32894, and IHC showed that GREM1 has significant prognostic value for BC patients. GREM1 is involved in immune and metabolism-related pathways. According to the TIDE algorithm, 61.0% of patients with low GREM1 expression responded well to immunotherapy, compared to only 13.3% in the high GREM1 expression group. High GREM1 expression was associated with sensitivity to cisplatin, docetaxel, gemcitabine, and vinblastine. Thus, GREM1 can predict prognosis and responses to immunotherapy and chemotherapy in BC patients, making it a potential biomarker and therapeutic target.
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Affiliation(s)
- Qingxin Yu
- Department of Pathology, Ningbo Clinical Pathology Diagnosis Center, Ningbo, 315211, Zhejiang, China.
| | - Shanshan Xu
- Department of Pathology, Ningbo Clinical Pathology Diagnosis Center, Ningbo, 315211, Zhejiang, China
| | - Shouxiang Weng
- Department of Pathology, Taizhou Hospital, Wenzhou Medical University, Linhai, 317000, Zhejiang, China
| | - Luxia Ye
- Department of Pathology, Taizhou Hospital, Wenzhou Medical University, Linhai, 317000, Zhejiang, China
| | - Haihong Zheng
- Department of Pathology, Taizhou Hospital, Wenzhou Medical University, Linhai, 317000, Zhejiang, China.
| | - Dengxiong Li
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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Kayama H, Takeda K. Regulation of intestinal epithelial homeostasis by mesenchymal cells. Inflamm Regen 2024; 44:42. [PMID: 39327633 PMCID: PMC11426228 DOI: 10.1186/s41232-024-00355-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 09/17/2024] [Indexed: 09/28/2024] Open
Abstract
The gastrointestinal tract harbors diverse microorganisms in the lumen. Epithelial cells segregate the luminal microorganisms from immune cells in the lamina propria by constructing chemical and physical barriers through the production of various factors to prevent excessive immune responses against microbes. Therefore, perturbations of epithelial integrity are linked to the development of gastrointestinal disorders. Several mesenchymal stromal cell populations, including fibroblasts, myofibroblasts, pericytes, and myocytes, contribute to the establishment and maintenance of epithelial homeostasis in the gut through regulation of the self-renewal, proliferation, and differentiation of intestinal stem cells. Recent studies have revealed alterations in the composition of intestinal mesenchymal stromal cells in patients with inflammatory bowel disease and colorectal cancer. A better understanding of the interplay between mesenchymal stromal cells and epithelial cells associated with intestinal health and diseases will facilitate identification of novel biomarkers and therapeutic targets for gastrointestinal disorders. This review summarizes the key findings obtained to date on the mechanisms by which functionally distinct mesenchymal stromal cells regulate epithelial integrity in intestinal health and diseases at different developmental stages.
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Affiliation(s)
- Hisako Kayama
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
- Institute for Advanced Co-Creation Studies, Osaka University, Suita, Osaka, 565-0871, Japan.
| | - Kiyoshi Takeda
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, Japan
- Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan
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17
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Dai S, Xu F, Xu X, Huang T, Wang Y, Wang H, Xie Y, Yue L, Zhao W, Xia Y, Gu J, Qian X. miR-455/GREM1 axis promotes colorectal cancer progression and liver metastasis by affecting PI3K/AKT pathway and inducing M2 macrophage polarization. Cancer Cell Int 2024; 24:235. [PMID: 38970064 PMCID: PMC11225248 DOI: 10.1186/s12935-024-03422-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 06/25/2024] [Indexed: 07/07/2024] Open
Abstract
BACKGROUND Colorectal cancer is among the most common malignant tumors affecting the gastrointestinal tract. Liver metastases, a complication present in approximately 50% of colorectal cancer patients, are a considerable concern. Recently, studies have revealed the crucial role of miR-455 in tumor pathogenesis. However, the effect of miR-455 on the progression of liver metastases in colorectal cancer remains controversial. As an antagonist of bone morphogenetic protein(BMP), Gremlin 1 (GREM1) may impact organogenesis, body patterning, and tissue differentiation. Nevertheless, the role of miR-455 in regulating GREM1 in colorectal cancer liver metastases and how miR-455/GREM1 axis influences tumour immune microenvironment is unclear. METHODS Bioinformatics analysis shows that miR-455/GREM1 axis plays crucial role in liver metastasis of intestinal cancer and predicts its possible mechanism. To investigate the impact of miR-455/GREM1 axis on the proliferation, invasion, and migration of colorectal cancer cells, colony formation assay, wound healing and transwell assay were examined in vitro. The Dual-Luciferase reporter gene assay and RNA pull-down assay confirmed a possible regulatory effect between miR-455 and GREM1. In vivo, colorectal cancer liver metastasis(CRLM) model mice was established to inquiry the effect of miR-455/GREM1 axis on tumor growth and macrophage polarization. The marker of macrophage polarization was tested using immunofluorescence(IF) and quantitative real-time polymerase chain reaction(qRT-PCR). By enzyme-linked immunosorbent assay (ELISA), cytokines were detected in culture medium supernatants. RESULTS We found that miR-455 and BMP6 expression was increased and GREM1 expression was decreased in liver metastase compared with primary tumor. miR-455/GREM1 axis promotes colorectal cancer cells proliferation, migration, invasion via affected PI3K/AKT pathway. Moreover, downregulating GREM1 augmented BMP6 expression in MC38 cell lines, inducing M2 polarization of macrophages, and promoting liver metastasis growth in CRLM model mice. CONCLUSION These data suggest that miR-455/GREM1 axis promotes colorectal cancer progression and liver metastasis by affecting PI3K/AKT pathway and inducing M2 macrophage polarization. These results offer valuable insights and direction for future research and treatment of CRLM.
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Affiliation(s)
- Shipeng Dai
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Fan Xu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Xiaozhang Xu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Tian Huang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Yiming Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Hongyu Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Yucheng Xie
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Lei Yue
- Hangzhou Institute of Medicine (HIM), Zhejiang Cancer Hospital, Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Wenhu Zhao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Yongxiang Xia
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
| | - Jian Gu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
| | - Xiaofeng Qian
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
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18
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Karam S, Gebreil A, Alksas A, Balaha HM, Khalil A, Ghazal M, Contractor S, El-Baz A. Insights into Personalized Care Strategies for Wilms Tumor: A Narrative Literature Review. Biomedicines 2024; 12:1455. [PMID: 39062028 PMCID: PMC11274555 DOI: 10.3390/biomedicines12071455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 06/17/2024] [Accepted: 06/26/2024] [Indexed: 07/28/2024] Open
Abstract
Wilms tumor (WT), or nephroblastoma, is the predominant renal malignancy in the pediatric population. This narrative review explores the evolution of personalized care strategies for WT, synthesizing critical developments in molecular diagnostics and treatment approaches to enhance patient-specific outcomes. We surveyed recent literature from the last five years, focusing on high-impact research across major databases such as PubMed, Scopus, and Web of Science. Diagnostic advancements, including liquid biopsies and diffusion-weighted MRI, have improved early detection precision. The prognostic significance of genetic markers, particularly WT1 mutations and miRNA profiles, is discussed. Novel predictive tools integrating genetic and clinical data to anticipate disease trajectory and therapy response are explored. Progressive treatment strategies, particularly immunotherapy and targeted agents such as HIF-2α inhibitors and GD2-targeted immunotherapy, are highlighted for their role in personalized treatment protocols, especially for refractory or recurrent WT. This review underscores the necessity for personalized management supported by genetic insights, with improved survival rates for localized disease exceeding 90%. However, knowledge gaps persist in therapies for high-risk patients and strategies to reduce long-term treatment-related morbidity. In conclusion, this narrative review highlights the need for ongoing research, particularly on the long-term outcomes of emerging therapies and integrating multi-omic data to inform clinical decision-making, paving the way for more individualized treatment pathways.
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Affiliation(s)
- Salma Karam
- Bioengineering Department, University of Louisville, Louisville, KY 40292, USA; (S.K.); (A.G.); (A.A.); (H.M.B.)
| | - Ahmad Gebreil
- Bioengineering Department, University of Louisville, Louisville, KY 40292, USA; (S.K.); (A.G.); (A.A.); (H.M.B.)
| | - Ahmed Alksas
- Bioengineering Department, University of Louisville, Louisville, KY 40292, USA; (S.K.); (A.G.); (A.A.); (H.M.B.)
| | - Hossam Magdy Balaha
- Bioengineering Department, University of Louisville, Louisville, KY 40292, USA; (S.K.); (A.G.); (A.A.); (H.M.B.)
| | - Ashraf Khalil
- College of Technological Innovation, Zayed University, Abu Dhabi 4783, United Arab Emirates;
| | - Mohammed Ghazal
- Electrical, Computer, and Biomedical Engineering Department, Abu Dhabi University, Abu Dhabi 59911, United Arab Emirates;
| | - Sohail Contractor
- Department of Radiology, University of Louisville, Louisville, KY 40202, USA;
| | - Ayman El-Baz
- Bioengineering Department, University of Louisville, Louisville, KY 40292, USA; (S.K.); (A.G.); (A.A.); (H.M.B.)
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19
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Vemuri K, Kumar S, Chen L, Verzi MP. Dynamic RNA polymerase II occupancy drives differentiation of the intestine under the direction of HNF4. Cell Rep 2024; 43:114242. [PMID: 38768033 PMCID: PMC11264335 DOI: 10.1016/j.celrep.2024.114242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 04/03/2024] [Accepted: 05/02/2024] [Indexed: 05/22/2024] Open
Abstract
Terminal differentiation requires massive restructuring of the transcriptome. During intestinal differentiation, the expression patterns of nearly 4,000 genes are altered as cells transition from progenitor cells in crypts to differentiated cells in villi. We identify dynamic occupancy of RNA polymerase II (Pol II) to gene promoters as the primary driver of transcriptomic shifts during intestinal differentiation in vivo. Changes in enhancer-promoter looping interactions accompany dynamic Pol II occupancy and are dependent upon HNF4, a pro-differentiation transcription factor. Using genetic loss-of-function, chromatin immunoprecipitation sequencing (ChIP-seq), and immunoprecipitation (IP) mass spectrometry, we demonstrate that HNF4 collaborates with chromatin remodelers and loop-stabilizing proteins and facilitates Pol II occupancy at hundreds of genes pivotal to differentiation. We also explore alternate mechanisms that drive differentiation gene expression and find that pause-release of Pol II and post-transcriptional mRNA stability regulate smaller subsets of differentially expressed genes. These studies provide insights into the mechanisms of differentiation in renewing adult tissue.
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Affiliation(s)
- Kiranmayi Vemuri
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA
| | - Sneha Kumar
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA
| | - Lei Chen
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China
| | - Michael P Verzi
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition & Health, Rutgers University, New Brunswick, NJ 08901, USA; NIEHS Center for Environmental Exposures and Disease (CEED), Rutgers EOHSI, Piscataway, NJ 08854, USA.
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20
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Malinauskas T, Moore G, Rudolf AF, Eggington H, Belnoue-Davis HL, El Omari K, Griffiths SC, Woolley RE, Duman R, Wagner A, Leedham SJ, Baldock C, Ashe HL, Siebold C. Molecular mechanism of BMP signal control by Twisted gastrulation. Nat Commun 2024; 15:4976. [PMID: 38862520 PMCID: PMC11167000 DOI: 10.1038/s41467-024-49065-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 05/22/2024] [Indexed: 06/13/2024] Open
Abstract
Twisted gastrulation (TWSG1) is an evolutionarily conserved secreted glycoprotein which controls signaling by Bone Morphogenetic Proteins (BMPs). TWSG1 binds BMPs and their antagonist Chordin to control BMP signaling during embryonic development, kidney regeneration and cancer. We report crystal structures of TWSG1 alone and in complex with a BMP ligand, Growth Differentiation Factor 5. TWSG1 is composed of two distinct, disulfide-rich domains. The TWSG1 N-terminal domain occupies the BMP type 1 receptor binding site on BMPs, whereas the C-terminal domain binds to a Chordin family member. We show that TWSG1 inhibits BMP function in cellular signaling assays and mouse colon organoids. This inhibitory function is abolished in a TWSG1 mutant that cannot bind BMPs. The same mutation in the Drosophila TWSG1 ortholog Tsg fails to mediate BMP gradient formation required for dorsal-ventral axis patterning of the early embryo. Our studies reveal the evolutionarily conserved mechanism of BMP signaling inhibition by TWSG1.
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Affiliation(s)
- Tomas Malinauskas
- Division of Structural Biology, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK.
| | - Gareth Moore
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK
| | - Amalie F Rudolf
- Division of Structural Biology, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK
| | - Holly Eggington
- Intestinal Stem Cell Biology Lab, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
- Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford National Institute for Health Research Biomedical Research Centre, Oxford, UK
| | - Hayley L Belnoue-Davis
- Intestinal Stem Cell Biology Lab, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
- Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford National Institute for Health Research Biomedical Research Centre, Oxford, UK
| | - Kamel El Omari
- Diamond Light Source, Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK
| | - Samuel C Griffiths
- Division of Structural Biology, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK
- Evotec (UK) Ltd., 90 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK
| | - Rachel E Woolley
- Division of Structural Biology, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK
- Etcembly Ltd., Atlas Building, Harwell Campus, OX11 0QX, UK
| | - Ramona Duman
- Diamond Light Source, Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK
| | - Armin Wagner
- Diamond Light Source, Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK
| | - Simon J Leedham
- Intestinal Stem Cell Biology Lab, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
- Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford National Institute for Health Research Biomedical Research Centre, Oxford, UK
| | - Clair Baldock
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, M13 9PT, UK
| | - Hilary L Ashe
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
| | - Christian Siebold
- Division of Structural Biology, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK.
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21
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Abstract
All cancers arise from normal cells whose progeny acquire the cancer-initiating mutations and epigenetic modifications leading to frank tumorigenesis. The identity of those "cells-of-origin" has historically been a source of controversy across tumor types, as it has not been possible to witness the dynamic events giving rise to human tumors. Genetically engineered mouse models (GEMMs) of cancer provide an invaluable substitute, enabling researchers to interrogate the competence of various naive cellular compartments to initiate tumors in vivo. Researchers using these models have relied on lineage-specific promoters, knowledge of preneoplastic disease states in humans, and technical advances allowing more precise manipulations of the mouse germline. These approaches have given rise to the emerging view that multiple lineages within a given organ may generate tumors with similar histopathology. Here, we review some of the key studies leading to this conclusion in solid tumors and highlight the biological and clinical ramifications.
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Affiliation(s)
- Jason R Pitarresi
- Division of Hematology and Oncology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01655, USA
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01655, USA
| | - Ben Z Stanger
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
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22
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Rakhmatullina AR, Zolotykh MA, Filina YV, Mingaleeva RN, Sagdeeva AR, Boulygina EA, Gafurbaeva DU, Bulatov ER, Rizvanov AA, Miftakhova RR. Development of a novel prostate Cancer-Stroma Sphere (CSS) model for In Vitro tumor microenvironment studies. Transl Oncol 2024; 44:101930. [PMID: 38520912 PMCID: PMC10981155 DOI: 10.1016/j.tranon.2024.101930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 02/21/2024] [Accepted: 03/05/2024] [Indexed: 03/25/2024] Open
Abstract
Tumor employs non-cancerous cells to gain beneficial features that promote growth and survival of cancer cells. Despite intensive research in the area of tumor microenvironment, there is still a lack of reliable and reproducible in vitro model for tumor and tumor-microenvironment cell interaction studies. Herein we report the successful development of a heterogeneous cancer-stroma sphere (CSS) model composed of prostate adenocarcinoma PC3 cells and immortalized mesenchymal stem cells (MSC). The CSS model demonstrated a structured spatial layout of the cells, with stromal cells concentrated at the center of the spheres and tumor cells located on the periphery. Significant increase in the levels of VEGFA, IL-10, and IL1a has been detected in the conditioned media of CSS as compared to PC3 spheres. Single cell RNA sequencing data revealed that VEGFA was secreted by MSC cells within heterogeneous spheroids. Enhanced expression of extracellular membrane (ECM) proteins was also shown for CSS-derived MSCs. Furthermore, we demonstrated that the multicellular architecture altered cancer cell response to chemotherapeutic agents: the inhibition of sphere formation by topotecan was 74.92 ± 4.56 % for PC3 spheres and 45.95 ± 7.84 % for CSS spheres (p < 0.01), docetaxel showed 37,51± 20,88 % and 15,67± 14,08 % inhibition, respectively (p < 0.05). Thus, CSS present an effective in vitro model for examining the extracellular matrix composition and cell-to-cell interactions within the tumor, as well as for evaluating the antitumor activity of drugs.
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Affiliation(s)
- Aigul R Rakhmatullina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Maria A Zolotykh
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Yulia V Filina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Rimma N Mingaleeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Aisylu R Sagdeeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Eugenia A Boulygina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Dina U Gafurbaeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Emil R Bulatov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
| | - Albert A Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; Division of Medical and Biological Sciences, Academy of Sciences of the Republic of Tatarstan, 420013, Kazan, Russia; I.K. Akhunbaev Kyrgyz state medical academy, 720020, Bishkek, Kyrgyzstan
| | - Regina R Miftakhova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia.
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23
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Jiang C, Zhou Q, Yi K, Yuan Y, Xie X. Colorectal cancer initiation: Understanding early-stage disease for intervention. Cancer Lett 2024; 589:216831. [PMID: 38574882 DOI: 10.1016/j.canlet.2024.216831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/18/2024] [Accepted: 03/21/2024] [Indexed: 04/06/2024]
Abstract
How tumors arise or the cause of precancerous lesions is a fundamental question in cancer biology. It is generally accepted that tumors originate from normal cells that undergo uncontrolled proliferation owing to genetic alterations. At the onset of adenoma formation, cancer driver mutations confer clonal growth advantage, enabling mutant cells to outcompete and eliminate the surrounding healthy cells. Hence, the development of precancerous lesions is not only attributed to the expansion of pre-malignant clones, but also relies on the relative fitness of mutated cells compared to the neighboring cells. Colorectal cancer (CRC) is an excellent model to investigate cancer origin as it follows a stereotypical process from mutant cell hyperplasia to adenoma formation and progression. Here, we review the evolving understanding of colonic tumor development, focusing on how cell intrinsic and extrinsic factors impact cell competition and the "clone war" between cancer-initiating cells and normal stem cells. We also discuss the promises and limitations of targeting cell competitiveness in cancer prevention and early intervention. The field of tumor initiation is currently in its infancy, elucidating the adenoma origin is crucial for designing effective prevention strategies and early treatments before cancer becomes incurable.
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Affiliation(s)
- Chao Jiang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Haining, 314400, China
| | - Qiujing Zhou
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Haining, 314400, China; The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310005, China
| | - Ke Yi
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Haining, 314400, China
| | - Ying Yuan
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
| | - Xin Xie
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Haining, 314400, China; Department of Medical Oncology, Cancer Institute and Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310029, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, 310058, China.
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24
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Tindall RR, Bailey-Lundberg JM, Cao Y, Ko TC. The TGF-β superfamily as potential therapeutic targets in pancreatic cancer. Front Oncol 2024; 14:1362247. [PMID: 38500662 PMCID: PMC10944957 DOI: 10.3389/fonc.2024.1362247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 02/15/2024] [Indexed: 03/20/2024] Open
Abstract
The transforming growth factor (TGF)-β superfamily has important physiologic roles and is dysregulated in many pathologic processes, including pancreatic cancer. Pancreatic cancer is one of the most lethal cancer diagnoses, and current therapies are largely ineffective due to tumor resistance and late-stage diagnosis with poor prognosis. Recent efforts are focused on the potential of immunotherapies in improving therapeutic results for patients with pancreatic cancer, among which TGF-β has been identified as a promising target. This review focuses on the role of TGF-β in the diseased pancreas and pancreatic cancer. It also aims to summarize the current status of therapies targeting the TGF-β superfamily and postulate potential future directions in targeting the TGF-β signaling pathways.
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Affiliation(s)
- Rachel R. Tindall
- McGovern Medical School, Department of Surgery, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Jennifer M. Bailey-Lundberg
- McGovern Medical School, Department of Anesthesiology, Critical Care, and Pain Medicine, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Yanna Cao
- McGovern Medical School, Department of Surgery, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Tien C. Ko
- McGovern Medical School, Department of Surgery, The University of Texas Health Science Center at Houston, Houston, TX, United States
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25
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Perez-Shibayama C, Gil-Cruz C, Cadosch N, Lütge M, Cheng HW, De Martin A, Frischmann K, Joachimbauer A, Onder L, Papadopoulou I, Papadopoulou C, Ring S, Krebs P, Vu VP, Nägele MP, Rossi VA, Parianos D, Zsilavecz VW, Cooper LT, Flammer A, Ruschitzka F, Rainer PP, Schmidt D, Ludewig B. Bone morphogenic protein-4 availability in the cardiac microenvironment controls inflammation and fibrosis in autoimmune myocarditis. NATURE CARDIOVASCULAR RESEARCH 2024; 3:301-316. [PMID: 39196111 PMCID: PMC11358008 DOI: 10.1038/s44161-024-00432-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 01/19/2024] [Indexed: 08/29/2024]
Abstract
Myocarditis is an inflammatory heart disease that leads to loss of cardiomyocytes and frequently precipitates fibrotic remodeling of the myocardium, culminating in heart failure. However, the molecular mechanisms underlying immune cell control and maintenance of tissue integrity in the inflamed cardiac microenvironment remain elusive. In this study, we found that bone morphogenic protein-4 (BMP4) gradients maintain cardiac tissue homeostasis by single-cell transcriptomics analyses of inflamed murine and human myocardial tissues. Cardiac BMP pathway dysregulation was reflected by reduced BMP4 serum concentration in patients with myocarditis. Restoration of BMP signaling by antibody-mediated neutralization of the BMP inhibitors gremlin-1 and gremlin-2 ameliorated T cell-induced myocardial inflammation in mice. Moreover, progression to inflammatory cardiomyopathy was blocked through the reduction of fibrotic remodeling and preservation of cardiomyocyte integrity. These results unveil the BMP4-gremlin axis as a druggable pathway for the treatment of myocardial inflammation, limiting the severe sequelae of cardiac fibrosis and heart failure.
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Affiliation(s)
| | - Cristina Gil-Cruz
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
- University Heart Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Nadine Cadosch
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Mechthild Lütge
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Hung-Wei Cheng
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Angelina De Martin
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Kira Frischmann
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Anna Joachimbauer
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
- University Heart Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Lucas Onder
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Iliana Papadopoulou
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Chrysa Papadopoulou
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Sandra Ring
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Philippe Krebs
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Vivian P Vu
- Institute of Pathology, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Matthias P Nägele
- University Heart Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Valentina A Rossi
- University Heart Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Danaë Parianos
- University Heart Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | | | - Leslie T Cooper
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Andreas Flammer
- University Heart Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Frank Ruschitzka
- University Heart Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Peter P Rainer
- Division of Cardiology, Medical University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
- St. Johann in Tirol General Hospital, St. Johann in Tirol, Austria
| | - Dörthe Schmidt
- University Heart Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Burkhard Ludewig
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
- University Heart Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
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26
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Stanger BZ, Wahl GM. Cancer as a Disease of Development Gone Awry. ANNUAL REVIEW OF PATHOLOGY 2024; 19:397-421. [PMID: 37832945 PMCID: PMC11486542 DOI: 10.1146/annurev-pathmechdis-031621-025610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2023]
Abstract
In the 160 years since Rudolf Virchow first postulated that neoplasia arises by the same law that regulates embryonic development, scientists have come to recognize the striking overlap between the molecular and cellular programs used by cancers and embryos. Advances in cancer biology and molecular techniques have further highlighted the similarities between carcinogenesis and embryogenesis, where cellular growth, differentiation, motility, and intercellular cross talk are mediated by common drivers and regulatory networks. This review highlights the many connections linking cancer biology and developmental biology to provide a deeper understanding of how a tissue's developmental history may both enable and constrain cancer cell evolution.
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Affiliation(s)
- Ben Z Stanger
- Division of Gastroenterology, Department of Medicine, Abramson Family Cancer Research Institute, and Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA;
| | - Geoffrey M Wahl
- Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA;
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27
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Chen J, Horiuchi S, Kuramochi S, Kawasaki T, Kawasumi H, Akiyama S, Arai T, Morinaga K, Kimura T, Kiyono T, Akutsu H, Ishida S, Umezawa A. Human intestinal organoid-derived PDGFRα + mesenchymal stroma enables proliferation and maintenance of LGR4 + epithelial stem cells. Stem Cell Res Ther 2024; 15:16. [PMID: 38229108 PMCID: PMC10792855 DOI: 10.1186/s13287-023-03629-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 12/27/2023] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND Intestinal epithelial cells derived from human pluripotent stem cells (hPSCs) are generally maintained and cultured as organoids in vitro because they do not exhibit adhesion when cultured. However, the three-dimensional structure of organoids makes their use in regenerative medicine and drug discovery difficult. Mesenchymal stromal cells are found near intestinal stem cells in vivo and provide trophic factors to regulate stem cell maintenance and proliferation, such as BMP inhibitors, WNT, and R-spondin. In this study, we aimed to use mesenchymal stromal cells isolated from hPSC-derived intestinal organoids to establish an in vitro culture system that enables stable proliferation and maintenance of hPSC-derived intestinal epithelial cells in adhesion culture. METHODS We established an isolation protocol for intestinal epithelial cells and mesenchymal stromal cells from hPSCs-derived intestinal organoids and a co-culture system for these cells. We then evaluated the intestinal epithelial cells and mesenchymal stromal cells' morphology, proliferative capacity, chromosomal stability, tumorigenicity, and gene expression profiles. We also evaluated the usefulness of the cells for pharmacokinetic and toxicity studies. RESULTS The proliferating intestinal epithelial cells exhibited a columnar form, microvilli and glycocalyx formation, cell polarity, and expression of drug-metabolizing enzymes and transporters. The intestinal epithelial cells also showed barrier function, transporter activity, and drug-metabolizing capacity. Notably, small intestinal epithelial stem cells cannot be cultured in adherent culture without mesenchymal stromal cells and cannot replaced by other feeder cells. Organoid-derived mesenchymal stromal cells resemble the trophocytes essential for maintaining small intestinal epithelial stem cells and play a crucial role in adherent culture. CONCLUSIONS The high proliferative expansion, productivity, and functionality of hPSC-derived intestinal epithelial cells may have potential applications in pharmacokinetic and toxicity studies and regenerative medicine.
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Affiliation(s)
- JunLong Chen
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
- Department of Advanced Pediatric Medicine, Tohoku University School of Medicine, Sendai, Japan
| | - Shinichiro Horiuchi
- Division of Pharmacology, National Institute of Health Sciences, Kawasaki, Japan
| | - So Kuramochi
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
| | - Tomoyuki Kawasaki
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
| | - Hayato Kawasumi
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
| | - Saeko Akiyama
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
- Department of Advanced Pediatric Medicine, Tohoku University School of Medicine, Sendai, Japan
| | - Tomoki Arai
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
| | - Kenichi Morinaga
- 1st Section, 1st Development Department, Food and Healthcare Business Development Unit, Business Development Division, Research & Business Development Center, Dai Nippon Printing Co., Ltd., Tokyo, Japan
| | - Tohru Kimura
- Laboratory of Stem Cell Biology, Department of BioSciences, Kitasato University School of Science, Kanagawa, Japan
| | - Tohru Kiyono
- Project for Prevention of HPV-Related Cancer, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan
| | - Hidenori Akutsu
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan
| | - Seiichi Ishida
- Division of Pharmacology, National Institute of Health Sciences, Kawasaki, Japan
- Graduate School of Engineering, Sojo University, Kumamoto, Japan
| | - Akihiro Umezawa
- Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.
- Department of Advanced Pediatric Medicine, Tohoku University School of Medicine, Sendai, Japan.
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28
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Wu H, Mu C, Xu L, Yu K, Shen L, Zhu W. Host-microbiota interaction in intestinal stem cell homeostasis. Gut Microbes 2024; 16:2353399. [PMID: 38757687 PMCID: PMC11110705 DOI: 10.1080/19490976.2024.2353399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 05/06/2024] [Indexed: 05/18/2024] Open
Abstract
Intestinal stem cells (ISCs) play a pivotal role in gut physiology by governing intestinal epithelium renewal through the precise regulation of proliferation and differentiation. The gut microbiota interacts closely with the epithelium through myriad of actions, including immune and metabolic interactions, which translate into tight connections between microbial activity and ISC function. Given the diverse functions of the gut microbiota in affecting the metabolism of macronutrients and micronutrients, dietary nutrients exert pronounced effects on host-microbiota interactions and, consequently, the ISC fate. Therefore, understanding the intricate host-microbiota interaction in regulating ISC homeostasis is imperative for improving gut health. Here, we review recent advances in understanding host-microbiota immune and metabolic interactions that shape ISC function, such as the role of pattern-recognition receptors and microbial metabolites, including lactate and indole metabolites. Additionally, the diverse regulatory effects of the microbiota on dietary nutrients, including proteins, carbohydrates, vitamins, and minerals (e.g. iron and zinc), are thoroughly explored in relation to their impact on ISCs. Thus, we highlight the multifaceted mechanisms governing host-microbiota interactions in ISC homeostasis. Insights gained from this review provide strategies for the development of dietary or microbiota-based interventions to foster gut health.
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Affiliation(s)
- Haiqin Wu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
| | - Chunlong Mu
- Food Informatics, AgResearch, Te Ohu Rangahau Kai, Palmerston North, New Zealand
| | - Laipeng Xu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
| | - Kaifan Yu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
| | - Le Shen
- Department of Surgery, The University of Chicago, Chicago, IL, USA
| | - Weiyun Zhu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
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29
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Zhou W, Yan K, Xi Q. BMP signaling in cancer stemness and differentiation. CELL REGENERATION (LONDON, ENGLAND) 2023; 12:37. [PMID: 38049682 PMCID: PMC10695912 DOI: 10.1186/s13619-023-00181-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 11/06/2023] [Indexed: 12/06/2023]
Abstract
The BMP (Bone morphogenetic protein) signaling pathway plays a central role in metazoan biology, intricately shaping embryonic development, maintaining tissue homeostasis, and influencing disease progression. In the context of cancer, BMP signaling exhibits context-dependent dynamics, spanning from tumor suppression to promotion. Cancer stem cells (CSCs), a modest subset of neoplastic cells with stem-like attributes, exert substantial influence by steering tumor growth, orchestrating therapy resistance, and contributing to relapse. A comprehensive grasp of the intricate interplay between CSCs and their microenvironment is pivotal for effective therapeutic strategies. Among the web of signaling pathways orchestrating cellular dynamics within CSCs, BMP signaling emerges as a vital conductor, overseeing CSC self-renewal, differentiation dynamics, and the intricate symphony within the tumor microenvironment. Moreover, BMP signaling's influence in cancer extends beyond CSCs, intricately regulating cellular migration, invasion, and metastasis. This multifaceted role underscores the imperative of comprehending BMP signaling's contributions to cancer, serving as the foundation for crafting precise therapies to navigate multifaceted challenges posed not only by CSCs but also by various dimensions of cancer progression. This article succinctly encapsulates the diverse roles of the BMP signaling pathway across different cancers, spanning glioblastoma multiforme (GBM), diffuse intrinsic pontine glioma (DIPG), colorectal cancer, acute myeloid leukemia (AML), lung cancer, prostate cancer, and osteosarcoma. It underscores the necessity of unraveling underlying mechanisms and molecular interactions. By delving into the intricate tapestry of BMP signaling's engagement in cancers, researchers pave the way for meticulously tailored therapies, adroitly leveraging its dualistic aspects-whether as a suppressor or promoter-to effectively counter the relentless march of tumor progression.
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Affiliation(s)
- Wei Zhou
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Kun Yan
- Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Qiaoran Xi
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
- Joint Graduate Program of Peking-Tsinghua-NIBS, Tsinghua University, Beijing, China.
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30
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Liu Q, Guo Z, Li G, Zhang Y, Liu X, Li B, Wang J, Li X. Cancer stem cells and their niche in cancer progression and therapy. Cancer Cell Int 2023; 23:305. [PMID: 38041196 PMCID: PMC10693166 DOI: 10.1186/s12935-023-03130-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 11/09/2023] [Indexed: 12/03/2023] Open
Abstract
High recurrence and metastasis rates and poor prognoses are the major challenges of current cancer therapy. Mounting evidence suggests that cancer stem cells (CSCs) play an important role in cancer development, chemoradiotherapy resistance, recurrence, and metastasis. Therefore, targeted CSC therapy has become a new strategy for solving the problems of cancer metastasis and recurrence. Since the properties of CSCs are regulated by the specific tumour microenvironment, the so-called CSC niche, which targets crosstalk between CSCs and their niches, is vital in our pursuit of new therapeutic opportunities to prevent cancer from recurring. In this review, we aim to highlight the factors within the CSC niche that have important roles in regulating CSC properties, including the extracellular matrix (ECM), stromal cells (e.g., associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and mesenchymal stem cells (MSCs)), and physiological changes (e.g., inflammation, hypoxia, and angiogenesis). We also discuss recent progress regarding therapies targeting CSCs and their niche to elucidate developments of more effective therapeutic strategies to eliminate cancer.
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Affiliation(s)
- Qiuping Liu
- Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466001, Henan, China
| | - Zongliang Guo
- Department of General Surgery, Shanxi Province Cancer Hospital, Affiliated of Shanxi Medical University, Taiyuan, 030013, Shanxi, China
| | - Guoyin Li
- Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466001, Henan, China
| | - Yunxia Zhang
- Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466001, Henan, China
| | - Xiaomeng Liu
- Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466001, Henan, China
| | - Bing Li
- Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466001, Henan, China
| | - Jinping Wang
- Department of Ultrasound, Shanxi Province People's Hospital, Taiyuan, 030012, Shanxi, China.
| | - Xiaoyan Li
- Department of blood transfusion, Shanxi Provincial People's Hospital, Taiyuan, 030032, Shanxi, China.
- Department of central laboratory, Shanxi Provincial People's Hospital, Taiyuan, 030032, Shanxi, China.
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31
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Vemuri K, Kumar S, Chen L, Verzi MP. Dynamic RNA Polymerase II Recruitment Drives Differentiation of the Intestine under the direction of HNF4. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.08.566322. [PMID: 37986803 PMCID: PMC10659318 DOI: 10.1101/2023.11.08.566322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
Terminal differentiation requires a massive restructuring of the transcriptome. During intestinal differentiation, the expression patterns of nearly 4000 genes are altered as cells transition from progenitor cells in crypts to differentiated cells in villi. We identified dynamic recruitment of RNA Polymerase II (Pol II) to gene promoters as the primary driver of transcriptomic shifts during intestinal differentiation in vivo. Changes in enhancer-promoter looping interactions accompany dynamic Pol II recruitment and are dependent upon HNF4, a pro-differentiation transcription factor. Using genetic loss-of- function, ChIP-seq and IP mass spectrometry, we demonstrate that HNF4 collaborates with chromatin remodelers and loop-stabilizing proteins and facilitates Pol II recruitment at hundreds of genes pivotal to differentiation. We also explore alternate mechanisms which drive differentiation gene expression and find pause-release of Pol II and post- transcriptional mRNA stability regulate smaller subsets of differentially expressed genes. These studies provide insights into the mechanisms of differentiation in a renewing adult tissue.
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Affiliation(s)
- Kiranmayi Vemuri
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA
| | - Sneha Kumar
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA
| | - Lei Chen
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China
| | - Michael P. Verzi
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
- Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition & Health, Rutgers University, New Brunswick, NJ 08901, USA
- NIEHS Center for Environmental Exposures and Disease (CEED), Rutgers EOHSI Piscataway, NJ 08854, USA
- Lead Contact
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32
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Brügger MD, Basler K. The diverse nature of intestinal fibroblasts in development, homeostasis, and disease. Trends Cell Biol 2023; 33:834-849. [PMID: 37080817 DOI: 10.1016/j.tcb.2023.03.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 02/28/2023] [Accepted: 03/13/2023] [Indexed: 04/22/2023]
Abstract
Only in recent years have we begun to appreciate the involvement of fibroblasts in intestinal development, tissue homeostasis, and disease. These insights followed the advent of single-cell transcriptomics that allowed researchers to explore the heterogeneity of intestinal fibroblasts in unprecedented detail. Since researchers often defined cell types and their associated function based on the biological process they studied, there are a plethora of partially overlapping markers for different intestinal fibroblast populations. This ambiguity complicates putting different research findings into context. Here, we provide a census on the function and identity of intestinal fibroblasts in mouse and human. We propose a simplified framework consisting of three colonic and four small intestinal fibroblast populations to aid navigating the diversity of intestinal fibroblasts.
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Affiliation(s)
- Michael David Brügger
- Department of Molecular Life Sciences, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
| | - Konrad Basler
- Department of Molecular Life Sciences, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
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33
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Sun J, Zhao J, Jiang F, Wang L, Xiao Q, Han F, Chen J, Yuan S, Wei J, Larsson SC, Zhang H, Dunlop MG, Farrington SM, Ding K, Theodoratou E, Li X. Identification of novel protein biomarkers and drug targets for colorectal cancer by integrating human plasma proteome with genome. Genome Med 2023; 15:75. [PMID: 37726845 PMCID: PMC10508028 DOI: 10.1186/s13073-023-01229-9] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 09/08/2023] [Indexed: 09/21/2023] Open
Abstract
BACKGROUND The proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) study to identify candidate protein markers and therapeutic targets for colorectal cancer (CRC). METHODS Protein quantitative trait loci (pQTLs) were derived from seven published genome-wide association studies (GWASs) on plasma proteome, and summary-level data were extracted for 4853 circulating protein markers. Genetic associations with CRC were obtained from a large-scale GWAS meta-analysis (16,871 cases and 26,328 controls), the FinnGen cohort (4957 cases and 304,197 controls), and the UK Biobank (9276 cases and 477,069 controls). Colocalization and summary-data-based MR (SMR) analyses were performed sequentially to verify the causal role of candidate proteins. Single cell-type expression analysis, protein-protein interaction (PPI), and druggability evaluation were further conducted to detect the specific cell type with enrichment expression and prioritize potential therapeutic targets. RESULTS Collectively, genetically predicted levels of 13 proteins were associated with CRC risk. Elevated levels of two proteins (GREM1, CHRDL2) and decreased levels of 11 proteins were associated with an increased risk of CRC, among which four (GREM1, CLSTN3, CSF2RA, CD86) were prioritized with the most convincing evidence. These protein-coding genes are mainly expressed in tissue stem cells, epithelial cells, and monocytes in colon tumor tissue. Two interactive pairs of proteins (GREM1 and CHRDL2; MMP2 and TIMP2) were identified to be involved in osteoclast differentiation and tumorigenesis pathways; four proteins (POLR2F, CSF2RA, CD86, MMP2) have been targeted for drug development on autoimmune diseases and other cancers, with the potentials of being repurposed as therapeutic targets for CRC. CONCLUSIONS This study identified several protein biomarkers to be associated with CRC risk and provided new insights into the etiology and promising targets for the development of screening biomarkers and therapeutic drugs for CRC.
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Affiliation(s)
- Jing Sun
- Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jianhui Zhao
- Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Fangyuan Jiang
- Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Lijuan Wang
- Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK
| | - Qian Xiao
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Fengyan Han
- Department of Pathology and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jie Chen
- Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shuai Yuan
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Jingsun Wei
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Susanna C Larsson
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Honghe Zhang
- Department of Pathology and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Malcolm G Dunlop
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Colon Cancer Genetics Group, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Susan M Farrington
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Kefeng Ding
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Evropi Theodoratou
- Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Xue Li
- Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK.
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34
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Pasquereau-Kotula E, Nigro G, Dingli F, Loew D, Poullet P, Xu Y, Kopetz S, Davis J, Peduto L, Robbe-Masselot C, Sansonetti P, Trieu-Cuot P, Dramsi S. Global proteomic identifies multiple cancer-related signaling pathways altered by a gut pathobiont associated with colorectal cancer. Sci Rep 2023; 13:14960. [PMID: 37696912 PMCID: PMC10495336 DOI: 10.1038/s41598-023-41951-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 09/04/2023] [Indexed: 09/13/2023] Open
Abstract
In this work, we investigated the oncogenic role of Streptococcus gallolyticus subsp. gallolyticus (SGG), a gut bacterium associated with colorectal cancer (CRC). We showed that SGG UCN34 accelerates colon tumor development in a chemically induced CRC murine model. Full proteome and phosphoproteome analysis of murine colons chronically colonized by SGG UCN34 revealed that 164 proteins and 725 phosphorylation sites were differentially regulated. Ingenuity Pathway Analysis (IPA) indicates a pro-tumoral shift specifically induced by SGG UCN34, as ~ 90% of proteins and phosphoproteins identified were associated with digestive cancer. Comprehensive analysis of the altered phosphoproteins using ROMA software revealed up-regulation of several cancer hallmark pathways such as MAPK, mTOR and integrin/ILK/actin, affecting epithelial and stromal colonic cells. Importantly, an independent analysis of protein arrays of human colon tumors colonized with SGG showed up-regulation of PI3K/Akt/mTOR and MAPK pathways, providing clinical relevance to our findings. To test SGG's capacity to induce pre-cancerous transformation of the murine colonic epithelium, we grew ex vivo organoids which revealed unusual structures with compact morphology. Taken together, our results demonstrate the oncogenic role of SGG UCN34 in a murine model of CRC associated with activation of multiple cancer-related signaling pathways.
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Affiliation(s)
- Ewa Pasquereau-Kotula
- Biology of Gram-Positive Pathogens Unit, Institut Pasteur, Université Paris Cité, CNRS UMR6047, 75015, Paris, France.
| | - Giulia Nigro
- Stroma, Inflammation and Tissue Repair Unit, Institut Pasteur, Université Paris Cité, INSERM U1224, 75015, Paris, France
- Microenvironment and Immunity Unit, Institut Pasteur, Université Paris Cité, INSERM U1224, 75015, Paris, France
| | - Florent Dingli
- Institut Curie, PSL Research University, CurieCoreTech Spectrométrie de Masse Protéomique, 75005, Paris, France
| | - Damarys Loew
- Institut Curie, PSL Research University, CurieCoreTech Spectrométrie de Masse Protéomique, 75005, Paris, France
| | - Patrick Poullet
- Institut Curie, Bioinformatics Core Facility (CUBIC), INSERM U900, PSL Research University, Mines Paris Tech, 75005, Paris, France
| | - Yi Xu
- Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA
- Department of Microbial Pathogenesis and Immunology, School of Medicine, Bryan, TX, USA
- Department of Microbiology and Molecular Genetics, University of Texas Health Science Center, Houston, TX, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jennifer Davis
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- University of Kansas, Kansas City, KS, USA
| | - Lucie Peduto
- Stroma, Inflammation and Tissue Repair Unit, Institut Pasteur, Université Paris Cité, INSERM U1224, 75015, Paris, France
| | - Catherine Robbe-Masselot
- Université de Lille, CNRS, UMR8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59000, Lille, France
| | - Philippe Sansonetti
- Institut Pasteur, Unité de Pathogénie Microbienne Moléculaire, INSERM U1202, and College de France, 75005, Paris, France
| | - Patrick Trieu-Cuot
- Biology of Gram-Positive Pathogens Unit, Institut Pasteur, Université Paris Cité, CNRS UMR6047, 75015, Paris, France
| | - Shaynoor Dramsi
- Biology of Gram-Positive Pathogens Unit, Institut Pasteur, Université Paris Cité, CNRS UMR6047, 75015, Paris, France.
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35
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Zhu D, Zhao D, Wang N, Cai F, Jiang M, Zheng Z. Current status and prospects of GREM1 research in cancer (Review). Mol Clin Oncol 2023; 19:69. [PMID: 37614374 PMCID: PMC10442762 DOI: 10.3892/mco.2023.2665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 03/21/2023] [Indexed: 08/25/2023] Open
Abstract
GREM1 is a secreted protein that antagonizes bone morphogenetic proteins (BMPs) and participates in critical biological processes, including embryonic development, organogenesis and tissue differentiation. Gremlin 1 (GREM1) is also an inhibitor of TGF-β and a ligand for vascular endothelial growth factor receptor 2. In addition, GREM1 can induce cells, participate in the process of epithelial-mesenchymal transition, and then participate in tumor development. GREM1 has a variety of biological functions and can participate in the malignant progression of a variety of tumors through the BMP signaling pathway. GREM1 also can inhibit TGF-β in some tumors, thereby inhibiting tumors, and its involvement in tumor development varies in different types of cancer. The present review examines the role and function of GREM1 in tumors. GREM1 is expressed in a variety of tumor types. GREM1 expression can affect the epithelial-mesenchymal transformation of tumor cells. GREM1 has been studied in breast and colon cancer, and its potential role is to promote cancer. However, in pancreatic cancer, which was found to act differently from other cancer types, overexpression of GREM1 inhibits tumor metastasis. The present review suggests that GREM1 can be a diagnostic and prognostic indicator. In future studies, the study of GREM1 based on single-cell sequencing technology will further clarify its role and function in tumors.
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Affiliation(s)
- Dantong Zhu
- Department of Medical Oncology, General Hospital of Northern Theater Command, Shenyang, Liaoning 110000, P.R. China
| | - Dong Zhao
- Department of Medical Oncology, General Hospital of Northern Theater Command, Shenyang, Liaoning 110000, P.R. China
| | - Naixue Wang
- Department of Oncology, General Hospital of Northern Theater Command, Jinzhou Medical University, Shenyang, Liaoning 121017, P.R. China
| | - Fei Cai
- Department of Oncology, General Hospital of Northern Theater Command, China Medical University, Shenyang, Liaoning 110000, P.R. China
| | - Mingzhe Jiang
- Department of Medical Oncology, General Hospital of Northern Theater Command, Shenyang, Liaoning 110000, P.R. China
| | - Zhendong Zheng
- Department of Medical Oncology, General Hospital of Northern Theater Command, Shenyang, Liaoning 110000, P.R. China
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36
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Gao Z, Houthuijzen JM, Ten Dijke P, Brazil DP. GREM1 signaling in cancer: tumor promotor and suppressor? J Cell Commun Signal 2023:10.1007/s12079-023-00777-4. [PMID: 37615860 DOI: 10.1007/s12079-023-00777-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 06/07/2023] [Indexed: 08/25/2023] Open
Abstract
GREMLIN1 (GREM1) is member of a family of structurally and functionally related secreted cysteine knot proteins, which act to sequester and inhibit the action of multifunctional bone morphogenetic proteins (BMPs). GREM1 binds directly to BMP dimers, thereby preventing BMP-mediated activation of BMP type I and type II receptors. Multiple reports identify the overexpression of GREM1 as a contributing factor in a broad range of cancers. Additionally, the GREM1 gene is amplified in a rare autosomal dominant inherited form of colorectal cancer. The inhibitory effects of GREM1 on BMP signaling have been linked to these tumor-promoting effects, including facilitating cancer cell stemness and the activation of cancer-associated fibroblasts. Moreover, GREM1 has been described to bind and signal to vascular endothelial growth factor receptor (VEGFR) and stimulate angiogenesis, as well as epidermal and fibroblast growth factor receptor (EGFR and FGFR) to elicit tumor-promoting effects in breast and prostate cancer, respectively. In contrast, a 2022 report revealed that GREM1 can promote an epithelial state in pancreatic cancers, thereby inhibiting pancreatic tumor growth and metastasis. In this commentary, we will review these disparate findings and attempt to provide clarity around the role of GREM1 signaling in cancer.
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Affiliation(s)
- Zhichun Gao
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Northern Ireland, BT9 7BL, UK
| | - Julia M Houthuijzen
- Oncode Institute, Division of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands
| | - Peter Ten Dijke
- Oncode Institute, Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
| | - Derek P Brazil
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Northern Ireland, BT9 7BL, UK.
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37
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Jiang PC, Xu LZ, Ning JZ, Cheng F. GREM1 is a potential biomarker for the progression and prognosis of bladder cancer. World J Surg Oncol 2023; 21:255. [PMID: 37605239 PMCID: PMC10463405 DOI: 10.1186/s12957-023-03128-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 07/29/2023] [Indexed: 08/23/2023] Open
Abstract
BACKGROUND Gremlin-1 (GREM1) is a protein closely related to tumor growth, although its function in bladder cancer (BCa) is currently unknown. Our first objective was to study the GREM1 treatment potential in BCa. METHODS BCa tissue samples were collected for the detection of GREM1 expression using Western blot analysis and Immunofluorescence staining. Association of GREM1 expression with clinicopathology and prognosis as detected by TCGA (The Cancer Genome Atlas) database. The functional investigation was tested by qRT-PCR, western blot analysis, CCK-8, cell apoptosis, wound healing, and transwell assays. The interaction between GREM1 and the downstream PI3K/AKT signaling pathway was assessed by Western blot analysis. RESULTS GREM1 exhibited high expression in BCa tissues and was linked to poor prognosis. Stable knockdown of GREM1 significantly inhibited BCa cell (T24 and 5637) proliferation, apoptosis, migratory, invasive, as well as epithelial-mesenchymal transition (EMT) abilities. GREM1 promotes the progression in BCa via PI3K/AKT signaling pathway. CONCLUSION Findings demonstrate that the progression-promoting effect of GREM1 in BCa, providing a novel biomarker for BCa-targeted therapy.
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Affiliation(s)
- Peng-Cheng Jiang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China
| | - Li-Zhe Xu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China
| | - Jin-Zhuo Ning
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China.
| | - Fan Cheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China.
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Suzuki T, Kilbey A, Casa-Rodríguez N, Lawlor A, Georgakopoulou A, Hayman H, Yin Swe KL, Nordin A, Cantù C, Vantourout P, Ridgway RA, Byrne RM, Chen L, Verzi MP, Gay DM, Gil Vázquez E, Belnoue-Davis HL, Gilroy K, Køstner AH, Kersten C, Thuwajit C, Andersen DK, Wiesheu R, Jandke A, Blyth K, Roseweir AK, Leedham SJ, Dunne PD, Edwards J, Hayday A, Sansom OJ, Coffelt SB. β-Catenin Drives Butyrophilin-like Molecule Loss and γδ T-cell Exclusion in Colon Cancer. Cancer Immunol Res 2023; 11:1137-1155. [PMID: 37309673 PMCID: PMC10398359 DOI: 10.1158/2326-6066.cir-22-0644] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 02/20/2023] [Accepted: 06/09/2023] [Indexed: 06/14/2023]
Abstract
Intraepithelial lymphocytes (IEL) expressing γδ T-cell receptors (γδTCR) play key roles in elimination of colon cancer. However, the precise mechanisms by which progressing cancer cells evade immunosurveillance by these innate T cells are unknown. Here, we investigated how loss of the Apc tumor suppressor in gut tissue could enable nascent cancer cells to escape immunosurveillance by cytotoxic γδIELs. In contrast with healthy intestinal or colonic tissue, we found that γδIELs were largely absent from the microenvironment of both mouse and human tumors, and that butyrophilin-like (BTNL) molecules, which can critically regulate γδIEL through direct γδTCR interactions, were also downregulated in tumors. We then demonstrated that β-catenin activation through loss of Apc rapidly suppressed expression of the mRNA encoding the HNF4A and HNF4G transcription factors, preventing their binding to promoter regions of Btnl genes. Reexpression of BTNL1 and BTNL6 in cancer cells increased γδIEL survival and activation in coculture assays but failed to augment their cancer-killing ability in vitro or their recruitment to orthotopic tumors. However, inhibition of β-catenin signaling via genetic deletion of Bcl9/Bcl9L in either Apc-deficient or mutant β-catenin mouse models restored Hnf4a, Hnf4g, and Btnl gene expression and γδ T-cell infiltration into tumors. These observations highlight an immune-evasion mechanism specific to WNT-driven colon cancer cells that disrupts γδIEL immunosurveillance and furthers cancer progression.
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Affiliation(s)
- Toshiyasu Suzuki
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Anna Kilbey
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Nuria Casa-Rodríguez
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Amy Lawlor
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Anastasia Georgakopoulou
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Hannah Hayman
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Kyi Lai Yin Swe
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Anna Nordin
- Wallenberg Centre for Molecular Medicine, Linköping University, Linköping, Sweden
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Claudio Cantù
- Wallenberg Centre for Molecular Medicine, Linköping University, Linköping, Sweden
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Pierre Vantourout
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, London, United Kingdom
- The Francis Crick Institute, London, United Kingdom
| | | | - Ryan M. Byrne
- School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, United Kingdom
| | - Lei Chen
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey
| | - Michael P. Verzi
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey
| | - David M. Gay
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
| | - Ester Gil Vázquez
- Nuffield Department of Medicine, Oxford University, Oxford, United Kingdom
| | | | - Kathryn Gilroy
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
| | | | - Christian Kersten
- Department of Research, Southern Hospital Trust, Kristiansand, Norway
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
| | - Chanitra Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Nakhon Pathom, Thailand
| | | | - Robert Wiesheu
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Anett Jandke
- The Francis Crick Institute, London, United Kingdom
| | - Karen Blyth
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Antonia K. Roseweir
- School of Medicine, Dentistry & Nursing, University of Glasgow, Glasgow, United Kingdom
| | - Simon J. Leedham
- Nuffield Department of Medicine, Oxford University, Oxford, United Kingdom
| | - Philip D. Dunne
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
- School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, United Kingdom
| | - Joanne Edwards
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Adrian Hayday
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, London, United Kingdom
- The Francis Crick Institute, London, United Kingdom
| | - Owen J. Sansom
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Seth B. Coffelt
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
- School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
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39
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Aglago EK, Kim A, Lin Y, Qu C, Evangelou M, Ren Y, Morrison J, Albanes D, Arndt V, Barry EL, Baurley JW, Berndt SI, Bien SA, Bishop DT, Bouras E, Brenner H, Buchanan DD, Budiarto A, Carreras-Torres R, Casey G, Cenggoro TW, Chan AT, Chang-Claude J, Chen X, Conti DV, Devall M, Diez-Obrero V, Dimou N, Drew D, Figueiredo JC, Gallinger S, Giles GG, Gruber SB, Gsur A, Gunter MJ, Hampel H, Harlid S, Hidaka A, Harrison TA, Hoffmeister M, Huyghe JR, Jenkins MA, Jordahl K, Joshi AD, Kawaguchi ES, Keku TO, Kundaje A, Larsson SC, Marchand LL, Lewinger JP, Li L, Lynch BM, Mahesworo B, Mandic M, Obón-Santacana M, Moreno V, Murphy N, Nan H, Nassir R, Newcomb PA, Ogino S, Ose J, Pai RK, Palmer JR, Papadimitriou N, Pardamean B, Peoples AR, Platz EA, Potter JD, Prentice RL, Rennert G, Ruiz-Narvaez E, Sakoda LC, Scacheri PC, Schmit SL, Schoen RE, Shcherbina A, Slattery ML, Stern MC, Su YR, Tangen CM, Thibodeau SN, Thomas DC, Tian Y, Ulrich CM, van Duijnhoven FJB, Van Guelpen B, Visvanathan K, Vodicka P, Wang J, White E, Wolk A, Woods MO, Wu AH, Zemlianskaia N, Hsu L, Gauderman WJ, Peters U, Tsilidis KK, Campbell PT. A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk. Cancer Res 2023; 83:2572-2583. [PMID: 37249599 PMCID: PMC10391330 DOI: 10.1158/0008-5472.can-22-3713] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 02/25/2023] [Accepted: 05/24/2023] [Indexed: 05/31/2023]
Abstract
Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
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Affiliation(s)
- Elom K. Aglago
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom
| | - Andre Kim
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Yi Lin
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Marina Evangelou
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom
| | - Yu Ren
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom
| | - John Morrison
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Volker Arndt
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Elizabeth L. Barry
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - James W. Baurley
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
- BioRealm LLC, Walnut, California
| | - Sonja I. Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Stephanie A. Bien
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - D. Timothy Bishop
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Emmanouil Bouras
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniel D. Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia
- Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Arif Budiarto
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
- Computer Science Department, School of Computer Science, Bina Nusantara University, Jakarta, Indonesia
| | - Robert Carreras-Torres
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Digestive Diseases and Microbiota Group, Girona Biomedical Research Institute (IDIBGI), Salt, Girona, Spain
| | - Graham Casey
- Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia
| | - Tjeng Wawan Cenggoro
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
| | - Andrew T. Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany
| | - Xuechen Chen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - David V. Conti
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Matthew Devall
- Department of Family Medicine, University of Virginia, Charlottesville, Virginia
| | - Virginia Diez-Obrero
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Niki Dimou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - David Drew
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jane C. Figueiredo
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Steven Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Graham G. Giles
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Stephen B. Gruber
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte California
| | - Andrea Gsur
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Marc J. Gunter
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Heather Hampel
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte California
| | - Sophia Harlid
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Akihisa Hidaka
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Tabitha A. Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jeroen R. Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Mark A. Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - Kristina Jordahl
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Amit D. Joshi
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Eric S. Kawaguchi
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Temitope O. Keku
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina
| | - Anshul Kundaje
- Department of Genetics, Stanford University, Stanford, California
- Department of Computer Science, Stanford University, Stanford, California
| | - Susanna C. Larsson
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | | | - Juan Pablo Lewinger
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, Virginia
| | - Brigid M. Lynch
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
- Physical Activity Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Bharuno Mahesworo
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
| | - Marko Mandic
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Mireia Obón-Santacana
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Victor Moreno
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Hongmei Nan
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indianapolis, Indiana
- IU Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana
| | - Rami Nassir
- Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia
| | - Polly A. Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington
| | - Shuji Ogino
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jennifer Ose
- Huntsman Cancer Institute, Salt Lake City, Utah
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
| | - Rish K. Pai
- Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Arizona
| | - Julie R. Palmer
- Department of Medicine, Boston University School of Medicine, Slone Epidemiology Center, Boston University, Boston, Massachusetts
| | - Nikos Papadimitriou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Bens Pardamean
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
| | - Anita R. Peoples
- Huntsman Cancer Institute, Salt Lake City, Utah
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
| | - Elizabeth A. Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - John D. Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington
- Research Centre for Hauora and Health, Massey University, Wellington, New Zealand
| | - Ross L. Prentice
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Gad Rennert
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
| | - Edward Ruiz-Narvaez
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan
| | - Lori C. Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Peter C. Scacheri
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio
| | | | - Robert E. Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Anna Shcherbina
- Department of Genetics, Stanford University, Stanford, California
- Department of Computer Science, Stanford University, Stanford, California
| | - Martha L. Slattery
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah
| | - Mariana C. Stern
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Yu-Ru Su
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Catherine M. Tangen
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Stephen N. Thibodeau
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Duncan C. Thomas
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Yu Tian
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- School of Public Health, Capital Medical University, Beijing, China
| | - Cornelia M. Ulrich
- Huntsman Cancer Institute, Salt Lake City, Utah
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
| | - Franzel JB van Duijnhoven
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands
| | - Bethany Van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Jun Wang
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Michael O. Woods
- Memorial University of Newfoundland, Discipline of Genetics, St. John's, Canada
| | - Anna H. Wu
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Natalia Zemlianskaia
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Department of Biostatistics, University of Washington, Seattle, Washington
| | - W. James Gauderman
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington
| | - Konstantinos K. Tsilidis
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Peter T. Campbell
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
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40
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Mthunzi L, Rowan SC, Kostyunina DS, Baugh JA, Knaus UG, McLoughlin P. Gremlin 1 is required for macrophage M2 polarization. Am J Physiol Lung Cell Mol Physiol 2023; 325:L270-L276. [PMID: 37401390 DOI: 10.1152/ajplung.00163.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/27/2023] [Accepted: 06/27/2023] [Indexed: 07/05/2023] Open
Abstract
Pro-proliferative, M2-like polarization of macrophages is a critical step in the development of fibrosis and remodeling in chronic lung diseases such as pulmonary fibrosis and pulmonary hypertension. Macrophages in healthy and diseased lungs express gremlin 1 (Grem1), a secreted glycoprotein that acts in both paracrine and autocrine manners to modulate cellular function. Increased Grem1 expression plays a central role in pulmonary fibrosis and remodeling, however, the role of Grem1 in M2-like polarization of macrophages has not previously been explored. The results reported here show that recombinant Grem1 potentiated M2-like polarization of mouse macrophages and bone marrow-derived macrophages (BMDMs) in response to the Th2 cytokines IL4 and IL13. Genetic depletion of Grem1 in BMDMs inhibited M2 polarization while exogenous gremlin 1 could partially rescue this effect. Taken together, these findings reveal that gremlin 1 is required for M2-like polarization of macrophages.NEW & NOTEWORTHY We show here that gremlin 1 potentiated M2 polarization of mouse bone marrow-derived macrophages (BMDMs) in response to the Th2 cytokines IL4 and IL13. Genetic depletion of Grem1 in BMDMs inhibited M2 polarization while exogenous gremlin 1 partially rescued this effect. Taken together, these findings reveal a previously unknown requirement for gremlin 1 in M2 polarization of macrophages and suggest a novel cellular mechanism promoting fibrosis and remodeling in lung diseases.
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Affiliation(s)
- Liberty Mthunzi
- School of Medicine, Health Sciences Centre, University College Dublin, Dublin, Ireland
| | - Simon C Rowan
- School of Medicine, Health Sciences Centre, University College Dublin, Dublin, Ireland
| | - Daria S Kostyunina
- School of Medicine, Health Sciences Centre, University College Dublin, Dublin, Ireland
| | - John A Baugh
- School of Medicine, Health Sciences Centre, University College Dublin, Dublin, Ireland
| | - Ulla G Knaus
- School of Medicine, Health Sciences Centre, University College Dublin, Dublin, Ireland
| | - Paul McLoughlin
- School of Medicine, Health Sciences Centre, University College Dublin, Dublin, Ireland
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41
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Xie Z, Zhou G, Zhang M, Han J, Wang Y, Li X, Wu Q, Li M, Zhang S. Recent developments on BMPs and their antagonists in inflammatory bowel diseases. Cell Death Discov 2023; 9:210. [PMID: 37391444 DOI: 10.1038/s41420-023-01520-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/15/2023] [Accepted: 06/22/2023] [Indexed: 07/02/2023] Open
Abstract
Inflammatory bowel diseases (IBDs), including ulcerative colitis, and Crohn's disease, are intestinal disorders characterized by chronic relapsing inflammation. A large proportion of patients with IBD will progress to develop colitis-associated colorectal cancer due to the chronic intestinal inflammation. Biologic agents that target tumour necrosis factor-α, integrin α4β7, and interleukin (IL)12/23p40 have been more successful than conventional therapies in treating IBD. However, drug intolerance and loss of response are serious drawbacks of current biologics, necessitating the development of novel drugs that target specific pathways in IBD pathogenesis. One promising group of candidate molecules are bone morphogenetic proteins (BMPs), members of the TGF-β family involved in regulating morphogenesis, homeostasis, stemness, and inflammatory responses in the gastrointestinal tract. Also worth examining are BMP antagonists, major regulators of these proteins. Evidence has shown that BMPs (especially BMP4/6/7) and BMP antagonists (especially Gremlin1 and follistatin-like protein 1) play essential roles in IBD pathogenesis. In this review, we provide an updated overview on the involvement of BMPs and BMP antagonists in IBD pathogenesis and in regulating the fate of intestinal stem cells. We also described the expression patterns of BMPs and BMP antagonists along the intestinal crypt-villus axis. Lastly, we synthesized available research on negative regulators of BMP signalling. This review summarizes recent developments on BMPs and BMP antagonists in IBD pathogenesis, which provides novel insights into future therapeutic strategies.
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Affiliation(s)
- Zhuo Xie
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Gaoshi Zhou
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Mudan Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Jing Han
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Ying Wang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Xiaoling Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Qirui Wu
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Manying Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Shenghong Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
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42
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McCarthy N, Tie G, Madha S, He R, Kraiczy J, Maglieri A, Shivdasani RA. Smooth muscle contributes to the development and function of a layered intestinal stem cell niche. Dev Cell 2023; 58:550-564.e6. [PMID: 36924771 PMCID: PMC10089980 DOI: 10.1016/j.devcel.2023.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 12/05/2022] [Accepted: 02/20/2023] [Indexed: 03/17/2023]
Abstract
Wnt and Rspondin (RSPO) signaling drives proliferation, and bone morphogenetic protein inhibitors (BMPi) impede differentiation, of intestinal stem cells (ISCs). Here, we identify the mouse ISC niche as a complex, multi-layered structure that encompasses distinct mesenchymal and smooth muscle populations. In young and adult mice, diverse sub-cryptal cells provide redundant ISC-supportive factors; few of these are restricted to single cell types. Niche functions refine during postnatal crypt morphogenesis, in part to oppose the dense aggregation of differentiation-promoting BMP+ sub-epithelial myofibroblasts at crypt-villus junctions. Muscularis mucosae, a specialized muscle layer, first appears during this period and supplements neighboring RSPO and BMPi sources. Components of this developing niche are conserved in human fetuses. The in vivo ablation of mouse postnatal smooth muscle increases BMP signaling activity, potently limiting a pre-weaning burst of crypt fission. Thus, distinct and progressively specialized mesenchymal cells together create the milieu that is required to propagate crypts during rapid organ growth and to sustain adult ISCs.
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Affiliation(s)
- Neil McCarthy
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
| | - Guodong Tie
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Shariq Madha
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Ruiyang He
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Judith Kraiczy
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Adrianna Maglieri
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Ramesh A Shivdasani
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02139, USA.
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43
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Banjac I, Maimets M, Jensen KB. Maintenance of high-turnover tissues during and beyond homeostasis. Cell Stem Cell 2023; 30:348-361. [PMID: 37028402 DOI: 10.1016/j.stem.2023.03.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 01/23/2023] [Accepted: 03/15/2023] [Indexed: 04/09/2023]
Abstract
Tissues with a high turnover rate produce millions of cells daily and have abundant regenerative capacity. At the core of their maintenance are populations of stem cells that balance self-renewal and differentiation to produce the adequate numbers of specialized cells required for carrying out essential tissue functions. Here, we compare and contrast the intricate mechanisms and elements of homeostasis and injury-driven regeneration in the epidermis, hematopoietic system, and intestinal epithelium-the fastest renewing tissues in mammals. We highlight the functional relevance of the main mechanisms and identify open questions in the field of tissue maintenance.
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Affiliation(s)
- Isidora Banjac
- The Novo Nordisk Foundation Center for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
| | - Martti Maimets
- The Novo Nordisk Foundation Center for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
| | - Kim B Jensen
- The Novo Nordisk Foundation Center for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
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44
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Che J, Yu S. Ecological niches for colorectal cancer stem cell survival and thrival. Front Oncol 2023; 13:1135364. [PMID: 37124519 PMCID: PMC10134776 DOI: 10.3389/fonc.2023.1135364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 03/17/2023] [Indexed: 05/02/2023] Open
Abstract
To date, colorectal cancer is still ranking top three cancer types severely threatening lives. According to cancer stem cell hypothesis, malignant colorectal lumps are cultivated by a set of abnormal epithelial cells with stem cell-like characteristics. These vicious stem cells are derived from intestinal epithelial stem cells or transformed by terminally differentiated epithelial cells when they accumulate an array of transforming genomic alterations. Colorectal cancer stem cells, whatever cell-of-origin, give rise to all morphologically and functionally heterogenous tumor daughter cells, conferring them with overwhelming resilience to intrinsic and extrinsic stresses. On the other hand, colorectal cancer stem cells and their daughter cells continuously participate in constructing ecological niches for their survival and thrival by communicating with adjacent stromal cells and circulating immune guardians. In this review, we first provide an overview of the normal cell-of-origin populations contributing to colorectal cancer stem cell reservoirs and the niche architecture which cancer stem cells depend on at early stage. Then we survey recent advances on how these aberrant niches are fostered by cancer stem cells and their neighbors. We also discuss recent research on how niche microenvironment affects colorectal cancer stem cell behaviors such as plasticity, metabolism, escape of immune surveillance as well as resistance to clinical therapies, therefore endowing them with competitive advantages compared to their normal partners. In the end, we explore therapeutic strategies available to target malignant stem cells.
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Affiliation(s)
- Jiayun Che
- Shanghai Institute of Precision Medicine, 9 Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shiyan Yu
- Shanghai Institute of Precision Medicine, 9 Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Oncology, 9 Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Shiyan Yu,
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45
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Osum M, Kalkan R. Cancer Stem Cells and Their Therapeutic Usage. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1436:69-85. [PMID: 36689167 DOI: 10.1007/5584_2022_758] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Cancer stem cells (CSC) have unique characteristics which include self-renewal, multi-directional differentiation capacity, quiescence/dormancy, and tumor-forming capability. These characteristics are referred to as the "stemness" properties. Tumor microenvironment contributes to CSC survival, function, and remaining them in an undifferentiated state. CSCs can form malignant tumors with heterogeneous phenotypes mediated by the tumor microenvironment. Therefore, the crosstalk between CSCs and tumor microenvironment can modulate tumor heterogeneity. CSCs play a crucial role in several biological processes, epithelial-mesenchymal transition (EMT), autophagy, and cellular stress response. In this chapter, we focused characteristics of cancer stem cells, reprogramming strategies cells into CSCs, and then we highlighted the contribution of CSCs to therapy resistance and cancer relapse and their potential of therapeutic targeting of CSCs.
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Affiliation(s)
- Meryem Osum
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Near East University, Nicosia, Cyprus
| | - Rasime Kalkan
- Department of Medical Genetics, Faculty of Medicine, Cyprus Health and Social Sciences University, Guzelyurt, Cyprus.
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46
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Flanagan DJ, Amirkhah R, Vincent DF, Gunduz N, Gentaz P, Cammareri P, McCooey AJ, McCorry AMB, Fisher NC, Davis HL, Ridgway RA, Lohuis J, Leach JDG, Jackstadt R, Gilroy K, Mariella E, Nixon C, Clark W, Hedley A, Markert EK, Strathdee D, Bartholin L, Redmond KL, Kerr EM, Longley DB, Ginty F, Cho S, Coleman HG, Loughrey MB, Bardelli A, Maughan TS, Campbell AD, Lawler M, Leedham SJ, Barry ST, Inman GJ, van Rheenen J, Dunne PD, Sansom OJ. Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features. Nat Commun 2022; 13:7551. [PMID: 36477656 PMCID: PMC9729215 DOI: 10.1038/s41467-022-35134-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 11/18/2022] [Indexed: 12/13/2022] Open
Abstract
The pro-tumourigenic role of epithelial TGFβ signalling in colorectal cancer (CRC) is controversial. Here, we identify a cohort of born to be bad early-stage (T1) colorectal tumours, with aggressive features and a propensity to disseminate early, that are characterised by high epithelial cell-intrinsic TGFβ signalling. In the presence of concurrent Apc and Kras mutations, activation of epithelial TGFβ signalling rampantly accelerates tumourigenesis and share transcriptional signatures with those of the born to be bad T1 human tumours and predicts recurrence in stage II CRC. Mechanistically, epithelial TGFβ signalling induces a growth-promoting EGFR-signalling module that synergises with mutant APC and KRAS to drive MAPK signalling that re-sensitise tumour cells to MEK and/or EGFR inhibitors. Together, we identify epithelial TGFβ signalling both as a determinant of early dissemination and a potential therapeutic vulnerability of CRC's with born to be bad traits.
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Affiliation(s)
- Dustin J Flanagan
- Cancer Research UK Beatson Institute, Glasgow, UK.
- Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia.
- Cancer Program, Biomedicine Discovery Institute, Monash University, Melbourne, Australia.
| | - Raheleh Amirkhah
- The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
| | | | - Nuray Gunduz
- Cancer Research UK Beatson Institute, Glasgow, UK
| | | | | | - Aoife J McCooey
- The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
| | - Amy M B McCorry
- The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
| | - Natalie C Fisher
- The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
| | - Hayley L Davis
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | | | - Jeroen Lohuis
- Department of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Joshua D G Leach
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Rene Jackstadt
- Cancer Research UK Beatson Institute, Glasgow, UK
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) and Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
| | | | - Elisa Mariella
- Department of Oncology, University of Torino, Candiolo, Torino, Italy
| | - Colin Nixon
- Cancer Research UK Beatson Institute, Glasgow, UK
| | | | - Ann Hedley
- Cancer Research UK Beatson Institute, Glasgow, UK
- University of Newcastle upon Tyne, Newcastle, UK
| | - Elke K Markert
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | | | - Keara L Redmond
- The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
| | - Emma M Kerr
- The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
| | - Daniel B Longley
- The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
| | - Fiona Ginty
- GE Global Research Center, Niskayuna, NY, USA
| | - Sanghee Cho
- GE Global Research Center, Niskayuna, NY, USA
| | - Helen G Coleman
- The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
- Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - Maurice B Loughrey
- The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
- Centre for Public Health, Queen's University Belfast, Belfast, UK
- Department of Cellular Pathology, Belfast Health and Social Care Trust, Belfast, UK
| | - Alberto Bardelli
- Department of Oncology, University of Torino, Candiolo, Torino, Italy
| | - Timothy S Maughan
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK
| | | | - Mark Lawler
- The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
| | - Simon J Leedham
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Simon T Barry
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK
| | - Gareth J Inman
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Jacco van Rheenen
- Department of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Philip D Dunne
- Cancer Research UK Beatson Institute, Glasgow, UK
- The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, UK.
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
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47
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Rahal Z, Sinjab A, Wistuba II, Kadara H. Game of clones: Battles in the field of carcinogenesis. Pharmacol Ther 2022; 237:108251. [PMID: 35850404 PMCID: PMC10249058 DOI: 10.1016/j.pharmthera.2022.108251] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 07/10/2022] [Accepted: 07/12/2022] [Indexed: 11/22/2022]
Abstract
Recent advances in bulk sequencing approaches as well as genomic decoding at the single-cell level have revealed surprisingly high somatic mutational burdens in normal tissues, as well as increased our understanding of the landscape of "field cancerization", that is, molecular and immune alterations in mutagen-exposed normal-appearing tissues that recapitulated those present in tumors. Charting the somatic mutational landscapes in normal tissues can have strong implications on our understanding of how tumors arise from mutagenized epithelium. Making sense of those mutations to understand the progression along the pathologic continuum of normal epithelia, preneoplasias, up to malignant tissues will help pave way for identification of ideal targets that can guide new strategies for preventing or eliminating cancers at their earliest stages of development. In this review, we will provide a brief history of field cancerization and its implications on understanding early stages of cancer pathogenesis and deviation from the pathologically "normal" state. The review will provide an overview of how mutations accumulating in normal tissues can lead to a patchwork of mutated cell clones that compete while maintaining an overall state of functional homeostasis. The review also explores the role of clonal competition in directing the fate of normal tissues and summarizes multiple mechanisms elicited in this phenomenon and which have been linked to cancer development. Finally, we highlight the importance of understanding mutations in normal tissues, as well as clonal competition dynamics (in both the epithelium and the microenvironment) and their significance in exploring new approaches to combatting cancer.
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Affiliation(s)
- Zahraa Rahal
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, USA
| | - Ansam Sinjab
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, USA
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, USA
| | - Humam Kadara
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, USA.
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48
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Luo H, Li M, Wang F, Yang Y, Wang Q, Zhao Y, Du F, Chen Y, Shen J, Zhao Q, Zeng J, Wang S, Chen M, Li X, Li W, Sun Y, Gu L, Wen Q, Xiao Z, Wu X. The role of intestinal stem cell within gut homeostasis: Focusing on its interplay with gut microbiota and the regulating pathways. Int J Biol Sci 2022; 18:5185-5206. [PMID: 35982910 PMCID: PMC9379405 DOI: 10.7150/ijbs.72600] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 07/29/2022] [Indexed: 12/05/2022] Open
Abstract
Intestinal stem cells (ISCs) play an important role in maintaining intestinal homeostasis via promoting a healthy gut barrier. Within the stem cell niche, gut microbiota linking the crosstalk of dietary influence and host response has been identified as a key regulator of ISCs. Emerging insights from recent research reveal that ISC and gut microbiota interplay regulates epithelial self-renewal. This article reviews the recent knowledge on the key role of ISC in their local environment (stem cell niche) associating with gut microbiota and their metabolites as well as the signaling pathways. The current progress of intestinal organoid culture is further summarized. Subsequently, the key challenges and future directions are discussed.
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Affiliation(s)
- Haoming Luo
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Fang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Yifei Yang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Qin Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Qianyun Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Jiuping Zeng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Shengpeng Wang
- State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Meijuan Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Xiaobing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Wanping Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Yuhong Sun
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Li Gu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Qinglian Wen
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Zhangang Xiao
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.,Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
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49
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Vasquez EG, Nasreddin N, Valbuena GN, Mulholland EJ, Belnoue-Davis HL, Eggington HR, Schenck RO, Wouters VM, Wirapati P, Gilroy K, Lannagan TRM, Flanagan DJ, Najumudeen AK, Omwenga S, McCorry AMB, Easton A, Koelzer VH, East JE, Morton D, Trusolino L, Maughan T, Campbell AD, Loughrey MB, Dunne PD, Tsantoulis P, Huels DJ, Tejpar S, Sansom OJ, Leedham SJ. Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia. Cell Stem Cell 2022; 29:1213-1228.e8. [PMID: 35931031 PMCID: PMC9592560 DOI: 10.1016/j.stem.2022.07.008] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 06/01/2022] [Accepted: 07/19/2022] [Indexed: 12/13/2022]
Abstract
Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5-ve regenerative stem cell populations (RSCs), characterized by fetal transcriptional profiles. Neoplasia hijacks regenerative signaling, so we assessed the distribution of CBCs and RSCs in mouse and human intestinal tumors. Using combined molecular-morphological analysis, we demonstrate variable expression of stem cell markers across a range of lesions. The degree of CBC-RSC admixture was associated with both epithelial mutation and microenvironmental signaling disruption and could be mapped across disease molecular subtypes. The CBC-RSC equilibrium was adaptive, with a dynamic response to acute selective pressure, and adaptability was associated with chemoresistance. We propose a fitness landscape model where individual tumors have equilibrated stem cell population distributions along a CBC-RSC phenotypic axis. Cellular plasticity is represented by position shift along this axis and is influenced by cell-intrinsic, extrinsic, and therapeutic selective pressures.
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Affiliation(s)
- Ester Gil Vasquez
- Wellcome Centre Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK
| | - Nadia Nasreddin
- Wellcome Centre Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK
| | - Gabriel N Valbuena
- Wellcome Centre Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK
| | - Eoghan J Mulholland
- Wellcome Centre Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK
| | | | - Holly R Eggington
- Wellcome Centre Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK
| | - Ryan O Schenck
- Wellcome Centre Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK
| | - Valérie M Wouters
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, Meibergdreef 9, 1105 Amsterdam, the Netherlands; Oncode Institute, Meibergdreef 9, 1105 Amsterdam, the Netherlands
| | - Pratyaksha Wirapati
- Swiss Institute for Bioinformatics, University of Lausanne, Lausanne, Switzerland
| | | | | | | | | | - Sulochana Omwenga
- Wellcome Centre Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK
| | - Amy M B McCorry
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK
| | - Alistair Easton
- Department of Oncology, Old Road Campus Research Building, Roosevelt Drive, University of Oxford, Oxford, UK
| | - Viktor H Koelzer
- Department of Pathology and Molecular Pathology, University and University Hospital Zürich, Rämistrasse 100, 8006 Zürich, Switzerland
| | - James E East
- Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, and Oxford NIHR Biomedical Research Centre, Oxford, UK
| | - Dion Morton
- Academic Department of Surgery, University of Birmingham, Birmingham, UK
| | - Livio Trusolino
- Candiolo Cancer Institute FPO IRCCS, 10060 Candiolo, Torino, Italy
| | - Timothy Maughan
- Department of Oncology, Old Road Campus Research Building, Roosevelt Drive, University of Oxford, Oxford, UK
| | | | - Maurice B Loughrey
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK
| | - Philip D Dunne
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK
| | - Petros Tsantoulis
- University of Geneva and Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland
| | - David J Huels
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, Meibergdreef 9, 1105 Amsterdam, the Netherlands; Oncode Institute, Meibergdreef 9, 1105 Amsterdam, the Netherlands
| | - Sabine Tejpar
- Molecular Digestive Oncology Unit, KU Leuven, Leuven, Belgium
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
| | - Simon J Leedham
- Wellcome Centre Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK; Department of Pathology and Molecular Pathology, University and University Hospital Zürich, Rämistrasse 100, 8006 Zürich, Switzerland.
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50
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Wu CWK, Reid M, Leedham S, Lui RN. The emerging era of personalized medicine in advanced colorectal cancer. J Gastroenterol Hepatol 2022; 37:1411-1425. [PMID: 35815339 PMCID: PMC7617119 DOI: 10.1111/jgh.15937] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 12/09/2022]
Abstract
Colorectal cancer (CRC) is a genetically heterogeneous disease with its pathogenesis often driven by varying genetic or epigenetic alterations. This has led to a substantial number of patients developing chemoresistance and treatment failure, resulting in a high mortality rate for advanced disease. Deep molecular analysis has allowed for the discovery of key intestinal signaling pathways which impacts colonic epithelial cell fate, and the integral role of the tumor microenvironment on cancer growth and dissemination. Through transitioning pre-clinical knowledge in research into clinical practice, many potential druggable targets within these pathways have been discovered in the hopes of overcoming the roadblocks encountered by conventional therapies. A personalized approach tailoring treatment according to the histopathological and molecular features of individual tumors can hopefully translate to better patient outcomes, and reduce the rate of recurrence in patients with advanced CRC. Herein, the latest understanding on the molecular science behind CRC tumorigenesis, and the potential treatment targets currently at the forefront of research are summarized.
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Affiliation(s)
- Claudia WK Wu
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
- Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China
| | - Madeleine Reid
- Translational Gastroenterology Unit, John Radcliffe hospital, University of Oxford, Oxford, United Kingdom
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Simon Leedham
- Translational Gastroenterology Unit, John Radcliffe hospital, University of Oxford, Oxford, United Kingdom
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Rashid N Lui
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
- Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China
- Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, China
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