1
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Zhang Z, Zhang Q, Wang Y. CAF-mediated tumor vascularization: From mechanistic insights to targeted therapies. Cell Signal 2025; 132:111827. [PMID: 40288665 DOI: 10.1016/j.cellsig.2025.111827] [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: 01/21/2025] [Revised: 04/15/2025] [Accepted: 04/17/2025] [Indexed: 04/29/2025]
Abstract
Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment (TME) and play a crucial role in tumor progression. The biological properties of tumors, such as drug resistance, vascularization, immunosuppression, and metastasis are closely associated with CAFs. During tumor development, CAFs contribute to tumor progression by remodeling the extracellular matrix (ECM), inhibiting immune cell function, promoting angiogenesis, and facilitating tumor cell growth, invasion, and metastasis. Studies have shown that CAFs can promote endothelial cell proliferation by directly secreting cytokines such as vascular endothelial growth factor (VEGF) and fibroblast Growth Factor (FGF), as well as through exosomes. CAFs also secrete the chemokine stromal cell-derived factor 1 (SDF-1) to recruit endothelial progenitor cells (EPCs) into the peripheral blood and guide their migration to the tumor periphery. Additionally, CAFs can induce tumor cells to transform into "endothelial cells" that participate in vascular wall formation. However, the precise mechanisms remain to be further investigated. Due to their widespread presence in various solid tumors and their tumor-promoting function, CAFs are emerging as therapeutic targets. In this review, we summarize the specific mechanisms through which CAFs promote angiogenesis and outline current therapeutic strategies targeting CAF-induced vascularization, ongoing clinical trials targeting CAFs, and discuss potential future treatment approaches. We hope this will contribute to the advancement of CAF-targeted tumor treatment strategies.
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Affiliation(s)
- Zhi Zhang
- Department of Neurosurgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Qing Zhang
- Department of Neurosurgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
| | - Yang Wang
- Department of Neurosurgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
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2
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Peña R, Baulida J. Snail1 as a key prognostic biomarker of cancer-associated fibroblasts in breast tumors. Biochim Biophys Acta Rev Cancer 2025; 1880:189316. [PMID: 40222423 DOI: 10.1016/j.bbcan.2025.189316] [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: 11/12/2024] [Revised: 04/03/2025] [Accepted: 04/04/2025] [Indexed: 04/15/2025]
Abstract
Accurate cancer diagnosis is crucial for selecting optimal treatments, yet current classification systems often include non-responders who receive ineffective therapies. Cancer-associated fibroblasts (CAFs) play a central role in tumor progression, and CAF biomarkers are increasingly recognized for their prognostic value. Recent studies have revealed significant heterogeneity within CAF populations, with distinct subtypes linked to different tumors and stages of disease. In this review, we summarize recent findings from patient samples and mouse models of breast cancer, focusing on gene signatures identified by single-cell RNA sequencing that define CAF subtypes and predict cancer prognosis. Additionally, we explore the genes and pathways regulated by Snail1, a transcription factor whose expression in breast and colon CAFs is associated with malignancy. Altogether these data emphasize the fibrotic and immunosuppressive roles of Snail1-expressing fibroblasts and unveil an undescribed streamlined Snail1-related gene signature in CAFs with prognostic potential in breast cancer and other solid tumors.
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Affiliation(s)
- Raúl Peña
- Cancer Research Program, associated unit IIBB-CSIC, Hospital del Mar Research Institute, Barcelona, Spain
| | - Josep Baulida
- Cancer Research Program, associated unit IIBB-CSIC, Hospital del Mar Research Institute, Barcelona, Spain.
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3
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Li C, Xing X, Li M, Liu Y, Huang S, Zhu T, Gu W, Yan B. Bile acids produced by gut microbiota activate TGR5 to promote colorectal liver metastasis progression by inducing MDSCs infiltration in liver. Int Immunopharmacol 2025; 158:114829. [PMID: 40367692 DOI: 10.1016/j.intimp.2025.114829] [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: 03/17/2025] [Revised: 04/27/2025] [Accepted: 05/06/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND CRLM (Colorectal liver metastasis), a prevalent form of distant metastasis in colorectal cancer, is a leading cause of mortality in affected patients. Despite advancements in immunotherapy for colorectal cancer, clinical benefits in CRLM patients remain limited. The immunosuppressive liver microenvironment plays a pivotal role in facilitating metastatic colonization and disease progression. METHODS We performed fecal metabolomics in ABX (antibiotic-treated) mice and single-cell RNA sequencing on hepatic tissues from four cohorts: CRC (colorectal cancer) , CRLM, LCA-fed CRC, and LCA-fed CRLM mice, to delineate intergroup immune heterogeneity. Cellular and molecular profiling across groups was conducted via Luminex multiplex assays, flow cytometry, and immunofluorescence. Integrated multi-omics analyses elucidated LCA-driven pathways modulating metastatic progression RESULTS: We demonstrated that LCA (lithocholic acid), a gut microbiota-derived metabolite, activates TGR5 in hepatic CAFs (cancer-associated fibroblasts) to upregulate CCL3 secretion. Elevated CCL3 levels subsequently recruit MDSCs (myeloid-derived suppressor cells) into metastatic niches. While MDSCs primarily suppress T-cell activation, we identified a paradoxical role of MDSC-derived CCL2 in attenuating immunosuppression via CCR2 signaling, suggesting a compensatory pro-inflammatory axis within the tumor microenvironment CONCLUSIONS: These findings suggest new immunotherapeutic strategies for the treatment of CRLM.
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Affiliation(s)
- Chenghui Li
- Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201799, China
| | - Xiao Xing
- Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201799, China
| | - Mingzhi Li
- Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201799, China
| | - Yonglei Liu
- Medical Research Center Laboratory, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201799, China
| | - Sinian Huang
- Department of Pathology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201799, China
| | - Ting Zhu
- Department of Pathology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201799, China
| | - Wei Gu
- Department of Obstetrics and Gynecology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201799, China
| | - Bin Yan
- Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201799, China.
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4
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Ai H, Nie R, Wang X. Pathway Enrichment-Based Unsupervised Learning Identifies Novel Subtypes of Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma. Interdiscip Sci 2025; 17:477-495. [PMID: 40272703 DOI: 10.1007/s12539-025-00705-7] [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: 04/15/2024] [Revised: 03/21/2025] [Accepted: 03/23/2025] [Indexed: 05/28/2025]
Abstract
Existing single-cell clustering methods are based on gene expressions that are susceptible to dropout events in single-cell RNA sequencing (scRNA-seq) data. To overcome this limitation, we proposed a pathway-based clustering method for single cells (scPathClus). scPathClus first transforms the single-cell gene expression matrix into a pathway enrichment matrix and generates its latent feature matrix. Based on the latent feature matrix, scPathClus clusters single cells using the method of community detection. Applying scPathClus to pancreatic ductal adenocarcinoma (PDAC) scRNA-seq datasets, we identified two types of cancer-associated fibroblasts (CAFs), termed csCAFs and gapCAFs, which highly expressed complement system and gap junction-related pathways, respectively. Spatial transcriptome analysis revealed that gapCAFs and csCAFs are located at cancer and non-cancer regions, respectively. Pseudotime analysis suggested a potential differentiation trajectory from csCAFs to gapCAFs. Bulk transcriptome analysis showed that gapCAFs-enriched tumors are more endowed with tumor-promoting characteristics and worse clinical outcomes, while csCAFs-enriched tumors confront stronger antitumor immune responses. Compared to established CAF subtyping methods, this method displays better prognostic relevance.
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Affiliation(s)
- Hongjing Ai
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
- Intelligent Pharmacy Interdisciplinary Research Center, China Pharmaceutical University, Nanjing, 211198, China
- Big Data Research Institute, China Pharmaceutical University, Nanjing, 211198, China
| | - Rongfang Nie
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
- Intelligent Pharmacy Interdisciplinary Research Center, China Pharmaceutical University, Nanjing, 211198, China
- Big Data Research Institute, China Pharmaceutical University, Nanjing, 211198, China
| | - Xiaosheng Wang
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
- Intelligent Pharmacy Interdisciplinary Research Center, China Pharmaceutical University, Nanjing, 211198, China.
- Big Data Research Institute, China Pharmaceutical University, Nanjing, 211198, China.
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5
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Fang Y, Tan C, Zheng Z, Yang J, Tang J, Guo R, Silli EK, Chen Z, Chen J, Ge R, Liu Y, Wen X, Liang J, Zhu Y, Jin Y, Li Q, Wang Y. The function of microRNA related to cancer-associated fibroblasts in pancreatic ductal adenocarcinoma. Biochem Pharmacol 2025; 236:116849. [PMID: 40056941 DOI: 10.1016/j.bcp.2025.116849] [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: 11/11/2024] [Revised: 02/13/2025] [Accepted: 03/03/2025] [Indexed: 03/17/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignant tumor characterized by a poor prognosis. A prominent feature of PDAC is the rich and dense stroma present in the tumor microenvironment (TME), which significantly hinders drug penetration. Cancer-associated fibroblasts (CAFs), activated fibroblasts originating from various cell sources, including pancreatic stellate cells (PSCs) and mesenchymal stem cells (MSCs), play a critical role in PDAC progression and TME formation. MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules that are frequently involved in tumorigenesis and progression, exhibiting either oncolytic or oncogenic activity. Increasing evidence suggests that aberrant expression of miRNAs can mediate interactions between cancer cells and CAFs, thereby providing novel therapeutic targets for PDAC treatment. In this review, we will focus on the potential roles of miRNAs that target CAFs or CAFs-derived exosomes in PDAC progression, highlighting the feasibility of therapeutic strategies aimed at restoring aberrantly expressed miRNAs associated with CAFs, offering new pathways for the clinical management of PDAC.
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Affiliation(s)
- Yaohui Fang
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Chunlu Tan
- Department of Pancreatic Surgery and General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Zhenjiang Zheng
- Department of Pancreatic Surgery and General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jianchen Yang
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA
| | - Jiali Tang
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Ruizhe Guo
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Epiphane K Silli
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Zhe Chen
- School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Jia Chen
- School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Ruyu Ge
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Yuquan Liu
- School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Xiuqi Wen
- School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Jingdan Liang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Yunfei Zhu
- School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Yutong Jin
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Qian Li
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Ying Wang
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
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6
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Dreyer SB, Beer P, Hingorani SR, Biankin AV. Improving outcomes of patients with pancreatic cancer. Nat Rev Clin Oncol 2025; 22:439-456. [PMID: 40329051 DOI: 10.1038/s41571-025-01019-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/04/2025] [Indexed: 05/08/2025]
Abstract
Research studies aimed at improving the outcomes of patients with pancreatic ductal adenocarcinoma (PDAC) have brought about limited progress, and in clinical practice, the optimized use of surgery, chemotherapy and supportive care have led to modest improvements in survival that have probably reached a plateau. As a result, PDAC is expected to be the second leading cause of cancer-related death in Western societies within a decade. The development of therapeutic advances in PDAC has been challenging owing to a lack of actionable molecular targets, a typically immunosuppressive microenvironment, and a disease course characterized by rapid progression and clinical deterioration. Yet, the progress in our understanding of PDAC and identification of novel therapeutic opportunities over the past few years is leading to a strong sense of optimism in the field. In this Perspective, we address the aforementioned challenges, including biological aspects of PDAC that make this malignancy particularly difficult to treat. We explore specific areas with potential for therapeutic advances, including targeting mutant KRAS, novel strategies to harness the antitumour immune response and approaches to early detection, and propose mechanisms to improve clinical trial design and to overcome various community and institutional barriers to progress.
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Affiliation(s)
- Stephan B Dreyer
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
- West of Scotland Hepato-Biliary and Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK
- Department of Hepatobiliary Surgery, Royal Liverpool University Hospital, Liverpool, UK
| | - Philip Beer
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
- Hull York Medical School, University of York, York, UK
| | - Sunil R Hingorani
- Department of Internal Medicine, Division of Hemotology/Oncology, University of Nebraska Medical Center, Omaha, NE, USA
- Pancreatic Cancer Center of Excellence, University of Nebraska Medical Center, Omaha, NE, USA
| | - Andrew V Biankin
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK.
- West of Scotland Hepato-Biliary and Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
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7
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Xiao Z, Puré E. The fibroinflammatory response in cancer. Nat Rev Cancer 2025; 25:399-425. [PMID: 40097577 DOI: 10.1038/s41568-025-00798-8] [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: 02/06/2025] [Indexed: 03/19/2025]
Abstract
Fibroinflammation refers to the highly integrated fibrogenic and inflammatory responses mediated by the concerted function of fibroblasts and innate immune cells in response to tissue perturbation. This process underlies the desmoplastic remodelling of the tumour microenvironment and thus plays an important role in tumour initiation, growth and metastasis. More specifically, fibroinflammation alters the biochemical and biomechanical signalling in malignant cells to promote their proliferation and survival and further supports an immunosuppressive microenvironment by polarizing the immune status of tumours. Additionally, the presence of fibroinflammation is often associated with therapeutic resistance. As such, there is increasing interest in targeting this process to normalize the tumour microenvironment and thus enhance the treatment of solid tumours. Herein, we review advances made in unravelling the complexity of cancer-associated fibroinflammation that can inform the rational design of therapies targeting this.
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Affiliation(s)
- Zebin Xiao
- Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Ellen Puré
- Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA, USA.
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8
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Ai B, Liang Y, Yan T, Lei Y. Exploration of immune cell heterogeneity by single-cell RNA sequencing and identification of secretory leukocyte protease inhibitor as an oncogene in pancreatic cancer. ENVIRONMENTAL TOXICOLOGY 2025; 40:879-890. [PMID: 38476085 DOI: 10.1002/tox.24200] [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] [Received: 11/02/2023] [Revised: 02/08/2024] [Accepted: 02/18/2024] [Indexed: 03/14/2024]
Abstract
Clinical outcomes remain unsatisfactory in patients with pancreatic cancer (PAC). In this study, through single-cell sequencing, we identified eight cell subpopulations in the tumor microenvironment (TME). Redimensional clustering of epithelial cells, myeloid cells, and cancer-associated fibroblasts (CAFs) revealed heterogeneity in the TME of PAC. Intercellular communication analysis showed strong direct interactions between matrix CAFs, inflammatory CAFs, and epithelial cells. Additionally, we found that the SPP1-associated pathway was activated in monocytes, whereas the vascular endothelial growth factor-associated pathway was activated in epithelial cells. These results improve the understanding of the TME of pancreatic cancer and provide a foundation for further studies on intratumoral heterogeneity. In addition, differentially expressed gene secretory leukocyte protease inhibitor (SLPI) was identified in pancreatic cancer, and functional experiments showed that SLPI had a strong impact on cell viability and apoptosis, which offers a potential therapy target for pancreatic cancer.
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Affiliation(s)
- Bolun Ai
- The Faculty of Hepatopancreatobiliary Surgery, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Yicheng Liang
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tao Yan
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yangyang Lei
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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9
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Yu X, Chen X, Chen W, Han X, Xie Q, Geng D, Guo G, Zhou L, Tang S, Chen J, Huang X, Zhong X. TGFβ2 Promotes the Construction of Fibrotic and Immunosuppressive Tumor Microenvironment in Pancreatic Adenocarcinoma: A Comprehensive Analysis. Mol Biotechnol 2025; 67:2562-2575. [PMID: 39044066 DOI: 10.1007/s12033-024-01219-1] [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: 03/30/2024] [Accepted: 06/10/2024] [Indexed: 07/25/2024]
Abstract
Pancreatic adenocarcinoma (PAAD) was characterized by dense fibrotic stroma and immunosuppressive tumor microenvironment (TME). TGFβ signaling pathways are highly activated in human cancers. However, the role of TGFβ2 in TME of PAAD remains to be elucidated. In this study, we showed that TGFβ2 was expressed at a relatively high level in PAAD tissues or cancer cells. Moreover, its high expression predicted unfavorable prognosis. In PAAD, gene set enrichment analysis showed that TGFβ2 correlated positively with leukocyte transendothelial migration, but negatively with aerobic metabolism, including oxidative phosphorylation. Results in Tumor and Immune System Interaction Database showed that TGFβ2 correlated with the infiltration of tumor-associated macrophages (TAMs), which could be attributed to that TGFβ2 promote CCL2 expression in PAAD. Moreover, correlation analysis showed that TGFβ2 could trigger cancer-associated fibroblasts (CAFs) activation in PAAD. The drug sensitivity analysis may indicate that patients with TGFβ2 high expression have higher sensitivity to chemotherapeutics, but the sensitivity to targeted drugs is still controversial. TGFβ2 could promote expansion of CAFs and infiltration of TAMs, thus participating in the construction of a fibrotic and immunosuppressive TME in PAAD. Targeting TGFβ2 could be a promising therapeutic approach, which needs to be elucidated by clinical and experimental evidences.
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Affiliation(s)
- Xiaofen Yu
- Department of Medical Oncology, Nanchang Third Hospital, Nanchang, 330000, Jiangxi, China
| | - Xuefen Chen
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou, China
| | - Wanxian Chen
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou, China
| | - Xiaosha Han
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou, China
| | - Qihu Xie
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou, China
| | - Deyi Geng
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou, China
| | - Genghong Guo
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou, China
| | - Linsa Zhou
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou, China
| | - Shijie Tang
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou, China
| | - Jiasheng Chen
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China.
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou, China.
| | - Xin Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
- Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, China.
- Department of Pancreatobiliary Surgery, Sun Yat-Sen University Cancer Center, GuangzhouGuangdong, 510060, China.
| | - Xiaoping Zhong
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China.
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou, China.
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10
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Fang B, Lu Y, Li X, Wei Y, Ye D, Wei G, Zhu Y. Targeting the tumor microenvironment, a new therapeutic approach for prostate cancer. Prostate Cancer Prostatic Dis 2025; 28:260-269. [PMID: 38565910 DOI: 10.1038/s41391-024-00825-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 03/17/2024] [Accepted: 03/21/2024] [Indexed: 04/04/2024]
Abstract
BACKGROUND A growing number of studies have shown that in addition to adaptive immune cells such as CD8 + T cells and CD4 + T cells, various other cellular components within prostate cancer (PCa) tumor microenvironment (TME), mainly tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs), have been increasingly recognized as important modulators of tumor progression and promising therapeutic targets. OBJECTIVE In this review, we aim to delineate the mechanisms by which TAMs, CAFs and MDSCs interact with PCa cells in the TME, summarize the therapeutic advancements targeting these cells and discuss potential new therapeutic avenues. METHODS We searched PubMed for relevant studies published through December 10 2023 on TAMs, CAFs and MDSCs in PCa. RESULTS TAMs, CAFs and MDSCs play a critical role in the tumorigenesis, progression, and metastasis of PCa. Moreover, they substantially mediate therapeutic resistance against conventional treatments including anti-androgen therapy, chemotherapy, and immunotherapy. Therapeutic interventions targeting these cellular components have demonstrated promising effects in preclinical models and several clinical trials for PCa, when administrated alone, or combined with other anti-cancer therapies. However, the lack of reliable biomarkers for patient selection and incomplete understanding of the mechanisms underlying the interactions between these cellular components and PCa cells hinder their clinical translation and utility. CONCLUSION New therapeutic strategies targeting TAMs, CAFs, and MDSCs in PCa hold promising prospects. Future research endeavors should focus on a more comprehensive exploration of the specific mechanisms by which these cells contribute to PCa, aiming to identify additional drug targets and conduct more clinical trials to validate the safety and efficacy of these treatment strategies.
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Affiliation(s)
- Bangwei Fang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Ying Lu
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Xiaomeng Li
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Yu Wei
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Dingwei Ye
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China
| | - Gonghong Wei
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Yao Zhu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Genitourinary Cancer Institute, Shanghai, 200032, China.
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11
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Kang M, Min C, Devarasou S, Shin JH. Classification of differentially activated groups of fibroblasts using morphodynamic and motile features. APL Bioeng 2025; 9:026116. [PMID: 40385989 PMCID: PMC12084086 DOI: 10.1063/5.0250502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 05/05/2025] [Indexed: 05/20/2025] Open
Abstract
Fibroblasts play essential roles in cancer progression, exhibiting activation states that can either promote or inhibit tumor growth. Understanding these differential activation states is critical for targeting the tumor microenvironment (TME) in cancer therapy. However, traditional molecular markers used to identify cancer-associated fibroblasts are limited by their co-expression across multiple fibroblast subtypes, making it difficult to distinguish specific activation states. Morphological and motility characteristics of fibroblasts reflect their underlying gene expression patterns and activation states, making these features valuable descriptors of fibroblast behavior. This study proposes an artificial intelligence-based classification framework to identify and characterize differentially activated fibroblasts by analyzing their morphodynamic and motile features. We extract these features from label-free live-cell imaging data of fibroblasts co-cultured with breast cancer cell lines using deep learning and machine learning algorithms. Our findings show that morphodynamic and motile features offer robust insights into fibroblast activation states, complementing molecular markers and overcoming their limitations. This biophysical state-based cellular classification framework provides a novel, comprehensive approach for characterizing fibroblast activation, with significant potential for advancing our understanding of the TME and informing targeted cancer therapies.
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Affiliation(s)
- Minwoo Kang
- Department of Mechanical Engineering, KAIST, 291 Daehak-Ro, Yuseong-Gu, Daejeon 34141, Republic of Korea
| | - Chanhong Min
- Department of Mechanical Engineering, KAIST, 291 Daehak-Ro, Yuseong-Gu, Daejeon 34141, Republic of Korea
| | - Somayadineshraj Devarasou
- Department of Mechanical Engineering, KAIST, 291 Daehak-Ro, Yuseong-Gu, Daejeon 34141, Republic of Korea
| | - Jennifer H. Shin
- Author to whom correspondence should be addressed:. Tel.: +82 42 350 3232
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12
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Gupta T, Murtaza M. Advancing targeted therapies in pancreatic cancer: Leveraging molecular abberrations for therapeutic success. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2025; 196:19-32. [PMID: 39988056 DOI: 10.1016/j.pbiomolbio.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 02/03/2025] [Accepted: 02/20/2025] [Indexed: 02/25/2025]
Abstract
Pancreatic cancer is one of the most deadly with poor prognosis and overall survival rate due to the dense stroma in the tumors which often is challenging for the delivery of drug to penetrate deep inside the tumor bed and usually results in the progression of cancer. The conventional treatment such as chemotherapy, radiotherapy or surgery shows a minimal benefit in the survival due to the drug resistance, poor penetration, less radiosensitivity or recurrence of tumor. There is an urgent demand to develop molecular-level targeted therapies to achieve therapeutic efficacy in the pancreatic ductal adenocarcinoma (PDAC) patients. The precision oncology focuses on the unique attributes of the patient such as epigenome, proteome, genome, microbiome, lifestyle and diet habits which contributes to promote oncogenesis. The targeted therapy helps to target the mutated proteins responsible for controlling growth, division and metastasis of tumor in the cancer cells. It is very important to consider all the attributes of the patient to provide the suitable personalized treatment to avoid any severe side effects. In this review, we have laid emphasis on the precision medicine; the utmost priority is to improve the survival of cancer patients by targeting molecular mutations through transmembrane proteins, inhibitors, signaling pathways, immunotherapy, gene therapy or the use of nanocarriers for the delivery at the tumor site. It will become beneficial therapeutic window to be considered for the advanced stage pancreatic cancer patients to prolong their survival rate.
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Affiliation(s)
- Tanvi Gupta
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan.
| | - Mohd Murtaza
- Fermentation & Microbial Biotechnology Division, CSIR- Indian Institute of Integrative Medicine, Jammu, 180016, India.
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13
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Wang Y, Wang Z, Mao X, Zhang H, Zhang L, Yang Y, Liu B, Li X, Luo F, Sun H. Cutting-edge technologies illuminate the neural landscape of cancer: Insights into tumor development. Cancer Lett 2025; 619:217667. [PMID: 40127813 DOI: 10.1016/j.canlet.2025.217667] [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: 01/26/2025] [Revised: 03/18/2025] [Accepted: 03/21/2025] [Indexed: 03/26/2025]
Abstract
Neurogenesis constitutes a pivotal facet of malignant tumors, wherein cancer and its therapeutic interventions possess the ability to reconfigure the nervous system, establishing a pathologic feedback loop that exacerbates tumor progression. Recent strides in high-resolution imaging, single-cell analysis, multi-omics technologies, and experimental models have opened unprecedented avenues in cancer neuroscience. This comprehensive review summarizes the latest advancements of these emerging technologies in elucidating the biological mechanisms underlying tumor initiation, invasion, metastasis, and the dynamic heterogeneity of the tumor microenvironment(TME), with a specific focus on neuron-glial-tumor interactions in glioblastoma(GBM) and other neurophilic cancers. Moreover, we innovatively propose target screening processes based on sequencing technologies and database frameworks. It rigorously evaluates ongoing clinical trial drugs and efficacy while spotlighting characteristic cells in the central and peripheral TME, consolidating cancer biomarkers pivotal for future targeted therapies and management strategies. By integrating these cutting-edge findings, this review aims to offer fresh insights into tumor-nervous system interactions, establishing a robust foundation for forthcoming clinical advancements.
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Affiliation(s)
- Yajing Wang
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Guangdong Provincial Clinical Research Centre for Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China; Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zhaojun Wang
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Guangdong Provincial Clinical Research Centre for Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China; Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xinyuan Mao
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, China; The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hongrui Zhang
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Guangdong Provincial Clinical Research Centre for Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China; Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lu Zhang
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Guangdong Provincial Clinical Research Centre for Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China; Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yufei Yang
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Guangdong Provincial Clinical Research Centre for Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China; Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Beibei Liu
- The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xinxu Li
- The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Feiyang Luo
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Guangdong Provincial Clinical Research Centre for Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China; Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Haitao Sun
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Guangdong Provincial Clinical Research Centre for Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China; Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, China; Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou, China.
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14
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Zhang S, Zhang T, Kinsella GK, Curtin JF. A review of the efficacy of prostate cancer therapies against castration-resistant prostate cancer. Drug Discov Today 2025; 30:104384. [PMID: 40409404 DOI: 10.1016/j.drudis.2025.104384] [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: 02/11/2025] [Revised: 05/05/2025] [Accepted: 05/16/2025] [Indexed: 05/25/2025]
Abstract
The standard treatments for prostate cancer (PCa) include chemotherapy, hormone therapy, targeted therapies based on androgen receptor (AR) and/or gonadotropin-releasing hormone (GnRH) receptor antagonists, and radiation therapy. But PCa therapeutic resistance remains an unsolved challenge, leading to progression to castration-resistant prostate cancer (CRPC). Emerging PCa therapies - including poly(ADP-ribose) polymerase (PARP) inhibitors, AR crosstalk signalling pathway inhibitors, B-cell lymphoma 2 (BCL-2) inhibitors, cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitors, CRISPR/Cas9, epigenetic inhibitors, and nanotechnology-based drug-delivery approaches - provide promising targeted solutions. Targeted protein degradation therapy, particularly AR degradation therapies, effectively inhibits resistance at its source. This review summarises the established and emerging PCa therapies, focusing on discussing their efficacy in terms of PCa resistance with supporting experimental findings and the mechanisms of PCa drug resistance.
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Affiliation(s)
- Shengxin Zhang
- School of Food Science and Environmental Health, Technological University Dublin, Grangegorman, Dublin D07 ADY7, Ireland; Sustainability and Health Research Hub (SHRH), Technological University Dublin, Grangegorman, Dublin D07 H6K8, Ireland
| | - Tao Zhang
- School of Food Science and Environmental Health, Technological University Dublin, Grangegorman, Dublin D07 ADY7, Ireland; Sustainability and Health Research Hub (SHRH), Technological University Dublin, Grangegorman, Dublin D07 H6K8, Ireland
| | - Gemma K Kinsella
- School of Food Science and Environmental Health, Technological University Dublin, Grangegorman, Dublin D07 ADY7, Ireland; Sustainability and Health Research Hub (SHRH), Technological University Dublin, Grangegorman, Dublin D07 H6K8, Ireland.
| | - James F Curtin
- School of Food Science and Environmental Health, Technological University Dublin, Grangegorman, Dublin D07 ADY7, Ireland; Sustainability and Health Research Hub (SHRH), Technological University Dublin, Grangegorman, Dublin D07 H6K8, Ireland
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15
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Pentimalli TM, Schallenberg S, León-Periñán D, Legnini I, Theurillat I, Thomas G, Boltengagen A, Fritzsche S, Nimo J, Ruff L, Dernbach G, Jurmeister P, Murphy S, Gregory MT, Liang Y, Cordenonsi M, Piccolo S, Coscia F, Woehler A, Karaiskos N, Klauschen F, Rajewsky N. Combining spatial transcriptomics and ECM imaging in 3D for mapping cellular interactions in the tumor microenvironment. Cell Syst 2025; 16:101261. [PMID: 40220761 DOI: 10.1016/j.cels.2025.101261] [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: 07/12/2024] [Revised: 12/13/2024] [Accepted: 03/19/2025] [Indexed: 04/14/2025]
Abstract
Tumors are complex ecosystems composed of malignant and non-malignant cells embedded in a dynamic extracellular matrix (ECM). In the tumor microenvironment, molecular phenotypes are controlled by cell-cell and ECM interactions in 3D cellular neighborhoods (CNs). While their inhibition can impede tumor progression, routine molecular tumor profiling fails to capture cellular interactions. Single-cell spatial transcriptomics (ST) maps receptor-ligand interactions but usually remains limited to 2D tissue sections and lacks ECM readouts. Here, we integrate 3D ST with ECM imaging in serial sections from one clinical lung carcinoma to systematically quantify molecular states, cell-cell interactions, and ECM remodeling in CN. Our integrative analysis pinpointed known immune escape and tumor invasion mechanisms, revealing several druggable drivers of tumor progression in the patient under study. This proof-of-principle study highlights the potential of in-depth CN profiling in routine clinical samples to inform microenvironment-directed therapies. A record of this paper's transparent peer review process is included in the supplemental information.
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Affiliation(s)
- Tancredi Massimo Pentimalli
- Laboratory for Systems Biology of Regulatory Elements, Berlin Institute for Medical Systems Biology (BIMSB), Max-Delbrück-Centrum for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin
| | - Simon Schallenberg
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität Berlin, Berlin, Germany
| | - Daniel León-Periñán
- Laboratory for Systems Biology of Regulatory Elements, Berlin Institute for Medical Systems Biology (BIMSB), Max-Delbrück-Centrum for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Ivano Legnini
- Laboratory for Systems Biology of Regulatory Elements, Berlin Institute for Medical Systems Biology (BIMSB), Max-Delbrück-Centrum for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; Human Technopole, Milan, Italy
| | - Ilan Theurillat
- Laboratory for Systems Biology of Regulatory Elements, Berlin Institute for Medical Systems Biology (BIMSB), Max-Delbrück-Centrum for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Gwendolin Thomas
- Laboratory for Systems Biology of Regulatory Elements, Berlin Institute for Medical Systems Biology (BIMSB), Max-Delbrück-Centrum for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Anastasiya Boltengagen
- Laboratory for Systems Biology of Regulatory Elements, Berlin Institute for Medical Systems Biology (BIMSB), Max-Delbrück-Centrum for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Sonja Fritzsche
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Spatial Proteomics Group, Berlin, Germany; Humboldt-Universität zu Berlin, Institute of Biology, 10099 Berlin, Germany
| | - Jose Nimo
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Spatial Proteomics Group, Berlin, Germany; Humboldt-Universität zu Berlin, Institute of Biology, 10099 Berlin, Germany
| | | | - Gabriel Dernbach
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität Berlin, Berlin, Germany; Aignostics GmbH, Berlin, Germany; BIFOLD - Berlin Institute for the Foundations of Learning and Data, Berlin, Germany
| | | | | | | | - Yan Liang
- NanoString® Technologies, Inc, Seattle, WA, USA
| | | | - Stefano Piccolo
- Department of Molecular Medicine, University of Padua, Padua, Italy; IFOM ETS, the AIRC Institute of Molecular Oncology, Milan, Italy
| | - Fabian Coscia
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Spatial Proteomics Group, Berlin, Germany
| | - Andrew Woehler
- Systems Biology Imaging Platform, Berlin Institute for Medical Systems Biology (BIMSB), Max-Delbrück-Centrum for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA, USA
| | - Nikos Karaiskos
- Laboratory for Systems Biology of Regulatory Elements, Berlin Institute for Medical Systems Biology (BIMSB), Max-Delbrück-Centrum for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Frederick Klauschen
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin; BIFOLD - Berlin Institute for the Foundations of Learning and Data, Berlin, Germany; Institute of Pathology, Ludwig Maximilians Universität, Munich, Germany
| | - Nikolaus Rajewsky
- Laboratory for Systems Biology of Regulatory Elements, Berlin Institute for Medical Systems Biology (BIMSB), Max-Delbrück-Centrum for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin; German Center for Cardiovascular Research (DZHK), Site Berlin, Berlin, Germany; NeuroCure Cluster of Excellence, Berlin, Germany; German Cancer Consortium (DKTK), Berlin, Germany; National Center for Tumor Diseases (NCT), Site Berlin, Berlin, Germany.
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16
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Blümke J, Schameitat M, Verma A, Limbecker C, Arlt E, Kessler SM, Kielstein H, Krug S, Bazwinsky-Wutschke I, Haemmerle M. Innate Immunity and Platelets: Unveiling Their Role in Chronic Pancreatitis and Pancreatic Cancer. Cancers (Basel) 2025; 17:1689. [PMID: 40427186 PMCID: PMC12110028 DOI: 10.3390/cancers17101689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Revised: 05/10/2025] [Accepted: 05/14/2025] [Indexed: 05/29/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal forms of cancer, characterized by a highly desmoplastic tumor microenvironment. One main risk factor is chronic pancreatitis (CP). Progression of CP to PDAC is greatly influenced by persistent inflammation promoting genomic instability, acinar-ductal metaplasia, and pancreatic intraepithelial neoplasia (PanIN) formation. Components of the extracellular matrix, including immune cells, can modulate this progression phase. This includes cells of the innate immune system, such as natural killer (NK) cells, macrophages, dendritic cells, mast cells, neutrophils, and myeloid-derived suppressor cells (MDSCs), either promoting or inhibiting tumor growth. On one hand, innate immune cells can trigger inflammatory responses that support tumor progression by releasing cytokines and growth factors, fostering tumor cell proliferation, invasion, and metastasis. On the other hand, they can also activate immune surveillance mechanisms, which can limit tumor development. For example, NK cells are cytotoxic innate lymphoid cells that are able to kill tumor cells, and active dendritic cells are crucial for a functioning anti-tumor immune response. In contrast, mast cells and MDSCs rather support a pro-tumorigenic tumor microenvironment that is additionally sustained by platelets. Once thought to play a role in hemostasis only, platelets are now recognized as key players in inflammation and cancer progression. By releasing cytokines, growth factors, and pro-angiogenic mediators, platelets help shape an immunosuppressive microenvironment that promotes fibrotic remodeling, tumor initiation, progression, metastasis, and immune evasion. Neutrophils and macrophages exist in different functional subtypes that can both act pro- and anti-tumorigenic. Understanding the complex interactions between innate immune cells, platelets, and early precursor lesions, as well as PDAC cells, is crucial for developing new therapeutic approaches that can harness the immune and potentially also the coagulation system to target and eliminate tumors, offering hope for improved patient outcomes.
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Affiliation(s)
- Juliane Blümke
- Institute of Pathology, Section of Experimental Pathology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06112 Halle (Saale), Germany;
| | - Moritz Schameitat
- Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany; (M.S.); (C.L.); (H.K.); (I.B.-W.)
| | - Atul Verma
- Department of Internal Medicine I, Medical Faculty, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany; (A.V.); (S.K.)
| | - Celina Limbecker
- Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany; (M.S.); (C.L.); (H.K.); (I.B.-W.)
| | - Elise Arlt
- Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany; (M.S.); (C.L.); (H.K.); (I.B.-W.)
| | - Sonja M. Kessler
- Institute of Pharmacy, Experimental Pharmacology for Natural Sciences, Faculty of Natural Sciences, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany;
| | - Heike Kielstein
- Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany; (M.S.); (C.L.); (H.K.); (I.B.-W.)
| | - Sebastian Krug
- Department of Internal Medicine I, Medical Faculty, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany; (A.V.); (S.K.)
- Department of Internal Medicine IV, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Ivonne Bazwinsky-Wutschke
- Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany; (M.S.); (C.L.); (H.K.); (I.B.-W.)
| | - Monika Haemmerle
- Institute of Pathology, Section of Experimental Pathology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06112 Halle (Saale), Germany;
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17
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Goto N, Agudo J, Yilmaz ÖH. Early immune evasion in colorectal cancer: interplay between stem cells and the tumor microenvironment. Trends Cancer 2025:S2405-8033(25)00112-8. [PMID: 40382216 DOI: 10.1016/j.trecan.2025.04.016] [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: 01/27/2025] [Revised: 04/23/2025] [Accepted: 04/24/2025] [Indexed: 05/20/2025]
Abstract
Most colorectal cancers (CRCs) are characterized by a low mutational burden and an immune-cold microenvironment, limiting the efficacy of immune checkpoint blockade (ICB) therapies. While advanced tumors exhibit diverse immune evasion mechanisms, emerging evidence suggests that aspects of immune escape arise much earlier, within precancerous lesions. In this review, we discuss how early driver mutations and epigenetic alterations contribute to the establishment of an immunosuppressive microenvironment in CRC. We also highlight the dynamic crosstalk between cancer cells, stromal niche cells, and immune cells driving immune evasion and liver metastasis. A deeper understanding of these early events may guide the development of more effective preventive and therapeutic strategies for CRC.
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Affiliation(s)
- Norihiro Goto
- Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology & Hepatology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.
| | - Judith Agudo
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center at Harvard, Boston, MA 02215, USA; Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA 02215, USA; New York Stem Cell Foundation, New York, NY 10019, USA
| | - Ömer H Yilmaz
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Beth Israel Deaconess Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
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18
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Li S, Zhou X, Feng H, Huang K, Chen M, Lin M, Lin H, Deng Z, Chen Y, Liao W, Zhang Z, Chen J, Guan B, Su T, Feng Z, Shu G, Yu A, Pan Y, Fu L. Deciphering the Immunomodulatory Function of GSN + Inflammatory Cancer-Associated Fibroblasts in Renal Cell Carcinoma Immunotherapy: Insights From Pan-Cancer Single-Cell Landscape and Spatial Transcriptomics Analysis. Cell Prolif 2025:e70062. [PMID: 40375605 DOI: 10.1111/cpr.70062] [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: 03/04/2025] [Revised: 04/13/2025] [Accepted: 05/02/2025] [Indexed: 05/18/2025] Open
Abstract
The heterogeneity of cancer-associated fibroblasts (CAFs) could affect the response to immune checkpoint inhibitor (ICI) therapy. However, limited studies have investigated the role of inflammatory CAFs (iCAFs) in ICI therapy using pan-cancer single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics sequencing (ST-seq) analysis. We performed pan-cancer scRNA-seq and ST-seq analyses to identify the subtype of GSN+ iCAFs, exploring its spatial distribution characteristics in the context of ICI therapy. The pan-cancer scRNA-seq and bulk RNA-seq data are incorporated to develop the Caf.Sig model, which predicts ICI response based on CAF gene signatures and machine learning approaches. Comprehensive scRNA-seq analysis, along with in vivo and in vitro experiments, investigates the mechanisms by which GSN+ iCAFs influence ICI efficacy. The Caf.Sig model demonstrates well performances in predicting ICI therapy response in pan-cancer patients. A higher proportion of GSN+ iCAFs is observed in ICI non-responders compared to responders in the pan-cancer landscape and clear cell renal cell carcinoma (ccRCC). Using real-world immunotherapy data, the Caf.Sig model accurately predicts ICI response in pan-cancer, potentially linked to interactions between GSN+ iCAFs and CD8+ Tex cells. ST-seq analysis confirms that interactions and cellular distances between GSN+ iCAFs and CD8+ exhausted T (Tex) cells impact ICI efficacy. In a co-culture system of primary CAFs, primary tumour cells and CD8+ T cells, downregulation of GSN on CAFs drives CD8+ T cells towards a dysfunctional state in ccRCC. In a subcutaneously tumour-grafted mouse model, combining GSN overexpression with ICI treatment achieves optimal efficacy in ccRCC. Our study provides the Caf.Sig model as an outperforming approach for patient selection of ICI therapy, and advances our understanding of CAF biology and suggests potential therapeutic strategies for upregulating GSN in CAFs in cancer immunotherapy.
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Affiliation(s)
- Shan Li
- Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Uro-Oncology Institute of Central South University, Changsha, Hunan, China
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Xinwei Zhou
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Haoqian Feng
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Kangbo Huang
- Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Minyu Chen
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Mingjie Lin
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Hansen Lin
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zebing Deng
- Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Uro-Oncology Institute of Central South University, Changsha, Hunan, China
| | - Yuhang Chen
- Department of Geniturinary Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Wuyuan Liao
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zhengkun Zhang
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jinwei Chen
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Bohong Guan
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Tian Su
- Department of Pediatric Intensive Care Unit (PICU), Guangdong Provincial People's Hospital Heyuan Hospital, Heyuan, Guangdong, China
| | - Zihao Feng
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Guannan Shu
- Department of Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou Institute of Pediatrics, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Anze Yu
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yihui Pan
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Liangmin Fu
- Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Uro-Oncology Institute of Central South University, Changsha, Hunan, China
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Disease, Changsha, Hunan, China
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19
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Deng S, Wang J, Zou F, Cheng D, Chen M, Gu J, Shi J, Yang J, Xue Y, Jiang Z, Qin L, Mao F, Chang X, Nie X, Liu L, Cao Y, Cai K. Palmitic Acid Accumulation Activates Fibroblasts and Promotes Matrix Stiffness in Colorectal Cancer. Cancer Res 2025; 85:1784-1802. [PMID: 39992719 PMCID: PMC12079102 DOI: 10.1158/0008-5472.can-24-2892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/27/2024] [Accepted: 02/17/2025] [Indexed: 02/26/2025]
Abstract
Obstructions can occur during any stage of colorectal cancer and correspond with poor prognosis. Obstructive colorectal cancer (OCRC) is harder and exhibits increased tumor budding and proliferation of myofibroblasts compared with nonobstructive colorectal cancer, suggesting that the occurrence of obstruction may be related to extracellular matrix (ECM) remodeling. In this study, we found that colorectal cancer and OCRC samples differed substantially in ECM composition, specifically in collagen (newly formed and mature) and proteoglycans (including glycosaminoglycan, hyaluronic acid, and chondroitin sulfate). OCRC also exhibited considerable changes in ECM biomechanics and collagen arrangement. Interestingly, OCRC samples presented a notable increase in matrix cancer-associated fibroblasts (mCAF). The abundance of mCAFs correlated with the accumulation of palmitic acid (PA), and high concentrations of PA increased the secretion of ECM-related proteins by mCAFs. Additionally, PA did not directly affect normal fibroblasts but rather activated the NF-κB pathway in tumor cells to stimulate secretion of CSF1, TGFβ1, and CXCL8, which promoted the activation of normal fibroblasts into mCAFs and exacerbated ECM stiffening. Drug screening with a natural compound library identified vanillylacetone as a potential inhibitor of PA-induced cytokine secretion and ECM stiffening. These findings highlight intratumoral PA accumulation as a key mechanism driving ECM alterations and OCRC progression and suggest that targeting this axis may be useful for treating patients with colorectal cancer with risk of obstruction. Significance: Palmitic acid accumulation activates the NF-κB pathway in colorectal cancer cells to promote cytokine secretion that facilitates the generation of matrix cancer-associated fibroblasts, driving extracellular matrix remodeling and development of obstructions.
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Affiliation(s)
- Shenghe Deng
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Falong Zou
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Denglong Cheng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mian Chen
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junnan Gu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianguo Shi
- Department of Gastrointestinal Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Yang
- Department of Gastrointestinal Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yifan Xue
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhenxin Jiang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Le Qin
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fuwei Mao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaona Chang
- Department of Pathology, Union Hospital, Tongji Medical, Huazhong University of Science and Technology, Wuhan, China
| | - Xiu Nie
- Department of Pathology, Union Hospital, Tongji Medical, Huazhong University of Science and Technology, Wuhan, China
| | - Li Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yinghao Cao
- Department of Digestive Surgical Oncology, Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Kailin Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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20
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Sharma S, Rodems BJ, Baker CD, Kaszuba CM, Franco EI, Smith BR, Ito T, Swovick K, Welle K, Zhang Y, Rock P, Chaves FA, Ghaemmaghami S, Calvi LM, Ganguly A, Burack WR, Becker MW, Liesveld JL, Brookes PS, Munger JC, Jordan CT, Ashton JM, Bajaj J. Taurine from tumour niche drives glycolysis to promote leukaemogenesis. Nature 2025:10.1038/s41586-025-09018-7. [PMID: 40369079 DOI: 10.1038/s41586-025-09018-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 04/14/2025] [Indexed: 05/16/2025]
Abstract
Signals from the microenvironment are known to be critical for development, stem cell self-renewal and oncogenic progression. Although some niche-driven signals that promote cancer progression have been identified1-5, concerted efforts to map disease-relevant microenvironmental ligands of cancer stem cell receptors have been lacking. Here, we use temporal single-cell RNA-sequencing (scRNA-seq) to identify molecular cues from the bone marrow stromal niche that engage leukaemia stem-enriched cells (LSCs) during oncogenic progression. We integrate these data with our human LSC RNA-seq and in vivo CRISPR screen of LSC dependencies6 to identify LSC-niche interactions that are essential for leukaemogenesis. These analyses identify the taurine-taurine transporter (TAUT) axis as a critical dependency of aggressive myeloid leukaemias. We find that cysteine dioxygenase type 1 (CDO1)-driven taurine biosynthesis is restricted to osteolineage cells, and increases during myeloid disease progression. Blocking CDO1 expression in osteolineage cells impairs LSC growth and improves survival outcomes. Using TAUT genetic loss-of-function mouse models and patient-derived acute myeloid leukaemia (AML) cells, we show that TAUT inhibition significantly impairs in vivo myeloid leukaemia progression. Consistent with elevated TAUT expression in venetoclax-resistant AML, TAUT inhibition synergizes with venetoclax to block the growth of primary human AML cells. Mechanistically, our multiomic approaches indicate that the loss of taurine uptake inhibits RAG-GTP dependent mTOR activation and downstream glycolysis. Collectively, our work establishes the temporal landscape of stromal signals during leukaemia progression and identifies taurine as a key regulator of myeloid malignancies.
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Affiliation(s)
- Sonali Sharma
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Benjamin J Rodems
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Cameron D Baker
- Genomics Research Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Christina M Kaszuba
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA
| | - Edgardo I Franco
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA
| | - Bradley R Smith
- Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, USA
| | - Takashi Ito
- Department of Bioscience and Technology, Graduate School of Bioscience and Technology, Fukui Prefectural University, Fukui, Japan
| | - Kyle Swovick
- Mass Spectrometry Resource Laboratory, University of Rochester, Rochester, NY, USA
| | - Kevin Welle
- Mass Spectrometry Resource Laboratory, University of Rochester, Rochester, NY, USA
| | - Yi Zhang
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Philip Rock
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Francisco A Chaves
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Sina Ghaemmaghami
- Mass Spectrometry Resource Laboratory, University of Rochester, Rochester, NY, USA
- Department of Biology, University of Rochester, Rochester, NY, USA
| | - Laura M Calvi
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Archan Ganguly
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA
| | - W Richard Burack
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Michael W Becker
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Jane L Liesveld
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Paul S Brookes
- Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY, USA
| | - Joshua C Munger
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, USA
| | - Craig T Jordan
- Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - John M Ashton
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Genomics Research Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Jeevisha Bajaj
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
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21
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Vadibeler S, Clarke S, Phyu SM, Parkes EE. Interactions between cancer-associated fibroblasts and the extracellular matrix in oesophageal cancer. Matrix Biol 2025:S0945-053X(25)00049-6. [PMID: 40379112 DOI: 10.1016/j.matbio.2025.05.003] [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: 04/07/2025] [Revised: 05/13/2025] [Accepted: 05/13/2025] [Indexed: 05/19/2025]
Abstract
Stromal components of the tumour microenvironment, such as cancer-associated fibroblasts (CAFs) and the extracellular matrix (ECM), are actively involved in tumorigenesis. CAFs and the ECM co-evolve with resultant molecular and mechanical pressure on tumour cells mediated by CAFs via the ECM. Meanwhile, ECM fibers determine CAF differentiation and activity, establishing a protumorigenic feed-forward loop. Oesophageal cancer carries a high morbidity and mortality, and curative surgical resection is only an option for a limited number of patients while early lymphatic spread and poor therapeutic responses are common. Although studies report marked heterogeneity in investigation of the stromal density of gastrointestinal cancers, it is generally accepted that oesophageal cancer is highly fibrotic, and stromal components like CAFs may outnumber cancer cells. Therefore, a comprehensive understanding of the reciprocal interaction between CAFs and the ECM in oesophageal cancer is essential to improving diagnostics and prognostication, as well as designing innovative anti-cancer strategies. Here, we summarise current understanding of oesophageal cancer from a stromal perspective. Then, we discuss that CAFs and the ECM in oesophageal cancer can independently and synergistically contribute to tumour progression and therapeutic resistance. We also summarise potential stromal targets that have been described in transcriptomic analyses, highlighting those validated in downstream experimental studies. Importantly, clinical translation of stromal-targeting strategies in oesophageal cancer is still in its infancy but holds significant promise for future therapeutic combinations.
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Affiliation(s)
- Subashan Vadibeler
- Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford; Department of Oncology, University of Oxford
| | - Shannique Clarke
- Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford; Department of Oncology, University of Oxford
| | - Su M Phyu
- Department of Oncology, University of Oxford
| | - Eileen E Parkes
- Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford; Department of Oncology, University of Oxford
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22
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Zou AE, Kongthong S, Mueller AA, Brenner MB. Fibroblasts in immune responses, inflammatory diseases and therapeutic implications. Nat Rev Rheumatol 2025:10.1038/s41584-025-01259-0. [PMID: 40369134 DOI: 10.1038/s41584-025-01259-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/08/2025] [Indexed: 05/16/2025]
Abstract
Once regarded as passive bystander cells of the tissue stroma, fibroblasts have emerged as active orchestrators of tissue homeostasis and disease. From regulating immunity and controlling tissue remodelling to governing cell growth and differentiation, fibroblasts assume myriad roles in guiding normal tissue development, maintenance and repair. By comparison, in chronic inflammatory diseases such as rheumatoid arthritis, fibroblasts recruit and sustain inflammatory leukocytes, become dominant producers of pro-inflammatory factors and catalyse tissue destruction. In other disease contexts, fibroblasts promote fibrosis and impair host control of cancer. Single-cell studies have uncovered striking transcriptional and functional heterogeneity exhibited by fibroblasts in both normal tissues and diseased tissues. In particular, advances in the understanding of fibroblast pathology in rheumatoid arthritis have shed light on pathogenic fibroblast states in other chronic diseases. The differentiation and activation of these fibroblast states is driven by diverse physical and chemical cues within the tissue microenvironment and by cell-intrinsic signalling and epigenetic mechanisms. These insights into fibroblast behaviour and regulation have illuminated therapeutic opportunities for the targeted deletion or modulation of pathogenic fibroblasts across many diseases.
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Affiliation(s)
- Angela E Zou
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Suppawat Kongthong
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Alisa A Mueller
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA and Palo Alto Veterans Affairs Health Care System, Palo Alto, CA, USA
| | - Michael B Brenner
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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23
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Faa G, Ziranu P, Pretta A, Cau F, Castagnola M, Spanu D, Saba G, D'Agata AP, Tiwari E, Suri JS, Scartozzi M, Saba L. Cancer-associated fibroblasts (CAFs) and plaque-associated fibroblasts (PAFs): Unraveling the cellular crossroads of atherosclerosis and cancer. Biomed Pharmacother 2025; 188:118145. [PMID: 40373629 DOI: 10.1016/j.biopha.2025.118145] [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: 11/11/2024] [Revised: 05/04/2025] [Accepted: 05/05/2025] [Indexed: 05/17/2025] Open
Abstract
Atherosclerosis is a complex process involving various cells and molecules within the atherosclerotic plaque. Recent evidence suggests that plaque-associated fibroblasts (PAFs), also known as atherosclerosis-associated fibroblasts (AAFs), might play a significant role in the development and progression of the disease. The microenvironment of the atherosclerotic plaque, resembling the tumor microenvironment (TME), includes various cellular populations like plaque-associated macrophages (PAMs), plaque-associated neutrophils (PANs), vascular smooth muscle cells (VSMCs), myeloid-derived suppressor cells (MDSCs), and PAFs. Similar to cancer-associated fibroblasts (CAFs) in tumors, PAFs exhibits a wide range of characteristics and functions. Their interactions with endothelial cells, smooth muscle cells, and other stromal cells, including adventitial fibroblast precursors, significantly influence atherosclerosis progression. Moreover, the ability of PAFs to express various markers such as alpha-SMA, Desmin, VEGF, and GFAP, highlights their diverse origins from different precursor cells, including vascular smooth muscle cells, endothelial cells, glial cells of the enteric nervous system, adventitial fibroblast precursors, as well as resident and circulating fibrocytes. This article explores the molecular interactions between PAFs, cells associated with atherosclerosis, and other stromal cells. It further examines the role of PAFs in the development and progression of atherosclerosis, and compares their features with those of CAFs. The research suggests that studying tumor-associated fibroblasts can help understand fibroblast subpopulations in atherosclerotic plaque. Identifying specific subpopulations could provide new insight into atherosclerosis complexity and lead to the development of innovative drugs for medical intervention.
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Affiliation(s)
- Gavino Faa
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari 09042, Italy.
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari 09042, Italy
| | - Flaviana Cau
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Massimo Castagnola
- Laboratory of Proteomics, Centro Europeo di Ricerca sul Cervello, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari 09042, Italy
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari 09042, Italy
| | - Alessandra Pia D'Agata
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari 09042, Italy
| | - Ekta Tiwari
- Department of Innovation. Global Biomedical Technologies, Inc., Roseville, CA 95661, USA
| | - Jasjit S Suri
- Department of ECE, Idaho State University, Pocatello, ID, 83209, USA; Department of CE, Graphics Era Deemed to be University, Dehradun 248002, India; University Center for Research & Development, Chandigarh University, Mohali, India; Symbiosis Institute of Technology, Nagpur Campus, Symbiosis International (Deemed University), Pune, INDIA; Stroke Diagnostic and Monitoring Division, AtheroPoint, Roseville, CA 95661, USA
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari 09042, Italy
| | - Luca Saba
- Department of Medical Sciences and Public Health, Unit of Radiology, University fo Cagliari, Cagliari, Italy
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24
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Wu T, Li X, Zheng F, Liu H, Yu Y. Intercellular communication between FAP+ fibroblasts and SPP1+ macrophages in prostate cancer via multi-omics. Front Immunol 2025; 16:1560998. [PMID: 40438108 PMCID: PMC12116517 DOI: 10.3389/fimmu.2025.1560998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 04/23/2025] [Indexed: 06/01/2025] Open
Abstract
Background Prostate cancer (PCa) presents substantial heterogeneity and unpredictability in its progression. Despite therapeutic advancements, mortality from advanced PCa remains a significant challenge. Understanding the intercellular communication within the tumor microenvironment (TME) is critical for uncovering mechanisms driving tumorigenesis and identifying novel therapeutic targets. Methods We employed an integrative approach combining bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics to investigate interactions between FAP+ fibroblasts and tumor-associated macrophages in PCa. Key findings were validated using immunohistochemical and immunofluorescence staining techniques. Results Analysis of 23,519 scRNA-seq data from 23 prostate samples revealed a pronounced accumulation of FAP+ fibroblasts in tumor tissues. Spatial transcriptomics and bulk RNA sequencing demonstrated strong associations between FAP+ fibroblasts and SPP1+ macrophages. Notably, tumor-specific intercellular signaling pathways, such as CSF1/CSF1R and CXCL/ACKR1, were identified, highlighting their potential role in fostering an immunosuppressive TME. Conclusion Our findings unveil a distinct pattern of crosstalk between FAP+ fibroblasts and SPP1+ macrophages in PCa, shedding light on potential therapeutic targets for advanced PCa.
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Affiliation(s)
- Tingting Wu
- Department of General Surgery, Shenzhen Qianhai Taikang Hospital, Shenzhen, China
| | - Xinyu Li
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Fei Zheng
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hanchao Liu
- Department of Andrology and Urology, Sir Run Shaw Hospital, affiliated with the Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yang Yu
- Department of General Surgery, Chifeng Hospital, Chifeng, Inner Mongolia, China
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25
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Liu Y, Sinjab A, Min J, Han G, Paradiso F, Zhang Y, Wang R, Pei G, Dai Y, Liu Y, Cho KS, Dai E, Basi A, Burks JK, Rajapakshe KI, Chu Y, Jiang J, Zhang D, Yan X, Guerrero PA, Serrano A, Li M, Hwang TH, Futreal A, Ajani JA, Solis Soto LM, Jazaeri AA, Kadara H, Maitra A, Wang L. Conserved spatial subtypes and cellular neighborhoods of cancer-associated fibroblasts revealed by single-cell spatial multi-omics. Cancer Cell 2025; 43:905-924.e6. [PMID: 40154487 PMCID: PMC12074878 DOI: 10.1016/j.ccell.2025.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 08/09/2024] [Accepted: 03/03/2025] [Indexed: 04/01/2025]
Abstract
Cancer-associated fibroblasts (CAFs) are a multifaceted cell population essential for shaping the tumor microenvironment (TME) and influencing therapy responses. Characterizing the spatial organization and interactions of CAFs within complex tissue environments provides critical insights into tumor biology and immunobiology. In this study, through integrative analyses of over 14 million cells from 10 cancer types across 7 spatial transcriptomics and proteomics platforms, we discover, validate, and characterize four distinct spatial CAF subtypes. These subtypes are conserved across cancer types and independent of spatial omics platforms. Notably, they exhibit distinct spatial organizational patterns, neighboring cell compositions, interaction networks, and transcriptomic profiles. Their abundance and composition vary across tissues, shaping TME characteristics, such as levels, distribution, and state composition of tumor-infiltrating immune cells, tumor immune phenotypes, and patient survival. This study enriches our understanding of CAF spatial heterogeneity in cancer and paves the way for novel approaches to target and modulate CAFs.
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Affiliation(s)
- Yunhe Liu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ansam Sinjab
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jimin Min
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Guangchun Han
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Francesca Paradiso
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yuanyuan Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ruiping Wang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Guangsheng Pei
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yibo Dai
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences (GSBS), Houston, TX 77030, USA
| | - Yang Liu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kyung Serk Cho
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Enyu Dai
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Akshay Basi
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jared K Burks
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kimal I Rajapakshe
- Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yanshuo Chu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jiahui Jiang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Daiwei Zhang
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Xinmiao Yan
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Paola A Guerrero
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Alejandra Serrano
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Mingyao Li
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Tae Hyun Hwang
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Andrew Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Luisa M Solis Soto
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Amir A Jazaeri
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Humam Kadara
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences (GSBS), Houston, TX 77030, USA.
| | - Anirban Maitra
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Linghua Wang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences (GSBS), Houston, TX 77030, USA; The James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Institute for Data Science in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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26
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Cheng Q, Zuo X, Wang Z, Lu W, Jiang Y, Liu J, Li X, Xu Q, Zhu S, Liu X, Song Y, Zhan P, Lv T. Intrapleural dual blockade of IL-6 and PD-L1 reprograms CAF dynamics and the tumor microenvironment in lung cancer-associated malignant pleural effusion. Respir Res 2025; 26:180. [PMID: 40349069 PMCID: PMC12065214 DOI: 10.1186/s12931-025-03263-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 04/29/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Malignant pleural effusion (MPE) is a severe complication in lung cancer, characterized by an immunosuppressive tumor microenvironment (TME) and limited therapeutic options. This study investigates the role of IL-6 in regulating immune suppression and tumor progression in MPE and evaluates the efficacy of dual IL-6 and PD-L1 blockade. METHODS IL-6 levels were measured in MPE and paired serum samples from lung cancer patients, and correlations with PD-L1 expression and clinical outcomes were analyzed using publicly available datasets. RNA sequencing and immune deconvolution were used to assess immune cell infiltration. CAFs and immune cell infiltration were further evaluated using flow cytometry, immunohistochemistry, and multiplex immunofluorescence. In vitro co-culture systems were employed to simulate the MPE microenvironment and explore IL-6 interactions with CAFs, as well as its regulatory effect on tumor cell PD-L1 expression. RESULTS IL-6 levels were significantly elevated in MPE compared to paired serum and correlated with higher PD-L1 expression and poor survival outcomes in lung cancer patients. In the MPE mouse model, combination therapy with IL-6 and PD-L1 blockade reduced MPE volume, tumor burden, and PD-L1 expression, while enhancing T cell infiltration and alleviating TME immunosuppression. IL-6 was found to drive a positive feedback loop with iCAFs, promoting an immunosuppressive environment. In vitro, IL-6 from the MPE upregulated tumor cell PD-L1 expression the IL-6/STAT3 pathway. CONCLUSION This study identifies IL-6 as a critical contributor of immune suppression and tumor progression in MPE. The combination of IL-6 and PD-L1 blockade effectively alleviated immunosuppression and reduced tumor burden, offering a potential therapeutic approach for MPE management.
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Affiliation(s)
- Qinpei Cheng
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xueying Zuo
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Zimu Wang
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Wanjun Lu
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yuxin Jiang
- Department of Respiratory and Critical Care Medicine, School of Medicine, Affiliated Jinling Hospital, Southeast University, Nanjing, China
| | - Jiaxin Liu
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xinying Li
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Qiuli Xu
- Department of Respiratory and Critical Care Medicine, School of Medicine, Affiliated Jinling Hospital, Southeast University, Nanjing, China
| | - Suhua Zhu
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xin Liu
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yong Song
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
- Department of Respiratory and Critical Care Medicine, School of Medicine, Affiliated Jinling Hospital, Southeast University, Nanjing, China.
| | - Ping Zhan
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Tangfeng Lv
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
- Department of Respiratory and Critical Care Medicine, School of Medicine, Affiliated Jinling Hospital, Southeast University, Nanjing, China.
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Hu H, Fan Y, Wang J, Zhang J, Lyu Y, Hou X, Cui J, Zhang Y, Gao J, Zhang T, Nan K. Single-cell technology for cell-based drug delivery and pharmaceutical research. J Control Release 2025; 381:113587. [PMID: 40032008 DOI: 10.1016/j.jconrel.2025.113587] [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: 10/16/2024] [Revised: 02/25/2025] [Accepted: 02/26/2025] [Indexed: 03/05/2025]
Abstract
Leveraging the capacity to precisely manipulate and analyze individual cells, single-cell technology has rapidly become an indispensable tool in the advancement of cell-based drug delivery systems and innovative cell therapies. This technology offers powerful means to address cellular heterogeneity and significantly enhance therapeutic efficacy. Recent breakthroughs in techniques such as single-cell electroporation, mechanical perforation, and encapsulation, particularly when integrated with microfluidics and bioelectronics, have led to remarkable improvements in drug delivery efficiency, reductions in cytotoxicity, and more precise targeting of therapeutic effects. Moreover, single-cell analyses, including advanced sequencing and high-resolution sensing, offer profound insights into complex disease mechanisms, the development of drug resistance, and the intricate processes of stem cell differentiation. This review summarizes the most significant applications of these single-cell technologies, highlighting their impact on the landscape of modern biomedicine. Furthermore, it provides a forward-looking perspective on future research directions aimed at further optimizing drug delivery strategies and enhancing therapeutic outcomes in the treatment of various diseases.
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Affiliation(s)
- Huihui Hu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China
| | - Yunlong Fan
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China; MicroTech Medical (Hangzhou) Co., Hangzhou 311100, China
| | - Jiawen Wang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China
| | - Jialu Zhang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China
| | - Yidan Lyu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China
| | - Xiaoqi Hou
- School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
| | - Jizhai Cui
- Department of Materials Science, Fudan University, Shanghai 200438, China; International Institute of Intelligent Nanorobots and Nanosystems, Fudan University, Shanghai 200438, China
| | - Yamin Zhang
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 117585, Singapore
| | - Jianqing Gao
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China
| | - Tianyuan Zhang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China.
| | - Kewang Nan
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China.
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28
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Tyler M, Gavish A, Barbolin C, Tschernichovsky R, Hoefflin R, Mints M, Puram SV, Tirosh I. The Curated Cancer Cell Atlas provides a comprehensive characterization of tumors at single-cell resolution. NATURE CANCER 2025:10.1038/s43018-025-00957-8. [PMID: 40341230 DOI: 10.1038/s43018-025-00957-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 03/24/2025] [Indexed: 05/10/2025]
Abstract
Recent years have seen a rapid proliferation of single-cell cancer studies, yet most of these studies profiled few tumors, limiting their statistical power. Combining data and results across studies holds great promise but also involves various challenges. We recently began to address these challenges by curating a large collection of cancer single-cell RNA-sequencing datasets, leveraging it for systematic analyses of tumor heterogeneity. Here we greatly extend this repository to 124 datasets for over 40 cancer types, together comprising 2,836 samples, with improved data annotations, visualizations and exploration. Using this vast cohort, we generate an updated map of recurrent expression programs in malignant cells and systematically quantify context-dependent gene expression and cell-cycle patterns across cell types and cancer types. These data, annotations and analysis results are all freely available for exploration and download through the Curated Cancer Cell Atlas, a central community resource that opens new avenues in cancer research.
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Affiliation(s)
- Michael Tyler
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany.
| | - Avishai Gavish
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Chaya Barbolin
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Roi Tschernichovsky
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
- Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel
| | - Rouven Hoefflin
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Michael Mints
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
| | - Sidharth V Puram
- Department of Otolaryngology-Head and Neck Surgery and Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
- The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, St. Louis, MO, USA
| | - Itay Tirosh
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
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Glapiński F, Zając W, Fudalej M, Deptała A, Czerw A, Sygit K, Kozłowski R, Badowska-Kozakiewicz A. The Role of the Tumor Microenvironment in Pancreatic Ductal Adenocarcinoma: Recent Advancements and Emerging Therapeutic Strategies. Cancers (Basel) 2025; 17:1599. [PMID: 40427098 PMCID: PMC12110676 DOI: 10.3390/cancers17101599] [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: 04/07/2025] [Revised: 04/30/2025] [Accepted: 05/06/2025] [Indexed: 05/29/2025] Open
Abstract
Pancreatic cancer (PC), with pancreatic ductal adenocarcinoma (PDAC) comprising about 90% of all cases, is one of the most aggressive and lethal solid tumors. PDAC remains one of the most significant challenges of oncology to this day due to its inadequate response to conventional treatment, gradual rise in incidence since 2004, and poor five-year survival rates. As cancer cells are the primary adversary in this uneven fight, they remain the primary research target. Nevertheless, increasing attention is being paid to the tumor microenvironment (TME). The most crucial TME constellation components are immune cells, especially macrophages, stellate cells and lymphocytes, fibroblasts, bacterial and fungal microflora, and neuronal cells. Depending on the particular phenotype of these cells, the composition of the microenvironment, and the cell ratio, patients can experience different disease outcomes and varying vulnerability to treatment approaches. This study aims to present the current knowledge and review the most up-to-date scientific findings regarding the microenvironment of PC. It contains detailed information on the structure and cellular composition of the stroma, including its impact on disease development, metastasis, and response to treatment, as well as the therapeutic opportunities that arise from targeting this tissue.
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Affiliation(s)
- Franciszek Glapiński
- Students’ Scientific Organization of Cancer Cell Biology, Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Weronika Zając
- Students’ Scientific Organization of Cancer Cell Biology, Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Marta Fudalej
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (M.F.); (A.D.)
- Department of Oncology, National Medical Institute of the Ministry of the Interior and Administration, 02-507 Warsaw, Poland
| | - Andrzej Deptała
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (M.F.); (A.D.)
| | - Aleksandra Czerw
- Department of Health Economics and Medical Law, Medical University of Warsaw, 02-091 Warsaw, Poland;
- Department of Economic and System Analyses, National Institute of Public Health NIH—National Research Institute, 00-791 Warsaw, Poland
| | - Katarzyna Sygit
- Faculty of Health Sciences, Calisia University, 62-800 Kalisz, Poland
| | - Remigiusz Kozłowski
- Department of Management and Logistics in Healthcare, Medical University of Lodz, 90-131 Lodz, Poland
| | - Anna Badowska-Kozakiewicz
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (M.F.); (A.D.)
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30
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Guo X, Bai J, Wang X, Guo S, Shang Z, Shao Z. Evoking the Cancer-immunity cycle by targeting the tumor-specific antigens in Cancer immunotherapy. Int Immunopharmacol 2025; 154:114576. [PMID: 40168803 DOI: 10.1016/j.intimp.2025.114576] [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: 02/08/2025] [Revised: 03/17/2025] [Accepted: 03/27/2025] [Indexed: 04/03/2025]
Abstract
Cancer-related deaths continue to rise, largely due to the suboptimal efficacy of current treatments. Fortunately, immunotherapy has emerged as a promising alternative, offering new hope for cancer patients. Among various immunotherapy approaches, targeting tumor-specific antigens (TSAs) has gained particular attention due to its demonstrated success in clinical settings. Despite these advancements, there are still gaps in our understanding of TSAs. Therefore, this review explores the life cycle of TSAs in cancer, the methods used to identify them, and recent advances in TSAs-targeted cancer therapies. Enhancing medical professionals' understanding of TSAs will help facilitate the development of more effective TSAs-based cancer treatments.
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Affiliation(s)
- Xiaomeng Guo
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Junqiang Bai
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Xinmiao Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Shutian Guo
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Zhengjun Shang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Department of Oral and Maxillofacial-Head and Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
| | - Zhe Shao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Day Surgery Center, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
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31
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Abate-Shen C, Politi K. The Evolution of Mouse Models of Cancer: Past, Present, and Future. Cold Spring Harb Perspect Med 2025; 15:a041736. [PMID: 38772706 PMCID: PMC12047742 DOI: 10.1101/cshperspect.a041736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2024]
Abstract
In the nearly 50 years since the original models of cancer first hit the stage, mouse models have become a major contributor to virtually all aspects of cancer research, and these have evolved well beyond simple transgenic or xenograft models to encompass a wide range of more complex models. As the sophistication of mouse models has increased, an explosion of new technologies has expanded the potential to both further develop and apply these models to address major challenges in cancer research. In the current era, cancer modeling has expanded to include nongermline genetically engineered mouse models (GEMMs), patient-derived models, organoids, and adaptations of the models better suited for cancer immunology research. New technologies that have transformed the field include the application of CRISPR-Cas9-mediated genome editing, in vivo imaging, and single-cell analysis to cancer modeling. Here, we provide a historical perspective on the evolution of mouse models of cancer, focusing on how far we have come in a relatively short time and how new technologies will shape the future development of mouse models of cancer.
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Affiliation(s)
- Cory Abate-Shen
- Departments of Molecular Pharmacology and Therapeutics, Urology, Pathology and Cell Biology, Medicine, and Systems Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York 10032, USA
| | - Katerina Politi
- Departments of Pathology and Internal Medicine (Section of Medical Oncology) and Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut 06405, USA
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32
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Mao Y, Li Y, Zheng Z, Xu Y, Ke M, He A, Liang F, Zhang K, Wang X, Gao W, Tian R. All-at-once spatial proteome profiling of complex tissue context with single-cell-type resolution by proximity proteomics. Cell Syst 2025:101291. [PMID: 40345200 DOI: 10.1016/j.cels.2025.101291] [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: 08/12/2024] [Revised: 01/01/2025] [Accepted: 04/11/2025] [Indexed: 05/11/2025]
Abstract
Spatial proteomics enables in-depth mapping of tissue architectures, mostly achieved by laser microdissection-mass spectrometry (LMD-MS) and antibody-based imaging. However, trade-offs among sampling precision, throughput, and proteome coverage still limit the applicability of these strategies. Here, we propose proximity labeling for spatial proteomics (PSPro) by combining precise antibody-targeted biotinylation and efficient affinity purification for all-at-once cell-type proteome capture with sub-micrometer resolution from single tissue slice. With fine-tuned labeling parameters, PSPro shows reliable performance in benchmarking against flow cytometry- and LMD-based proteomic workflows. We apply PSPro to tumor and spleen slices, enriching thousands of proteins containing known markers from ten cell types. We further incorporate LMD into PSPro to facilitate comparison of cell subpopulations from the same tissue slice, revealing spatial proteome heterogeneity of cancer cells and immune cells in pancreatic tumor. Collectively, PSPro converts the traditional "antibody-epitope" paradigm to an "antibody-cell-type proteome" for spatial biology in a user-friendly manner. A record of this paper's transparent peer review process is included in the supplemental information.
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Affiliation(s)
- Yiheng Mao
- Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, College of Science, Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen 518055, China
| | - Yuan Li
- Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, College of Science, Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen 518055, China
| | - Zhendong Zheng
- Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, College of Science, Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen 518055, China
| | - Yanfen Xu
- Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, College of Science, Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen 518055, China
| | - Mi Ke
- Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, College of Science, Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen 518055, China
| | - An He
- Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, College of Science, Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen 518055, China
| | - Fuchao Liang
- Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, College of Science, Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen 518055, China
| | - Keren Zhang
- Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, College of Science, Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen 518055, China
| | - Xi Wang
- Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, College of Science, Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen 518055, China
| | - Weina Gao
- Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, College of Science, Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen 518055, China
| | - Ruijun Tian
- Department of Chemistry and Research Center for Chemical Biology and Omics Analysis, College of Science, Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen 518055, China.
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33
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You E, Patel BK, Rojas AS, Sun S, Danaher P, Ho NI, Phillips IE, Raabe MJ, Song Y, Xu KH, Kocher JR, Richieri PM, Shin P, Taylor MS, Nieman LT, Greenbaum BD, Ting DT. LINE-1 ORF1p Mimics Viral Innate Immune Evasion Mechanisms in Pancreatic Ductal Adenocarcinoma. Cancer Discov 2025; 15:1063-1082. [PMID: 39919290 PMCID: PMC12046326 DOI: 10.1158/2159-8290.cd-24-1317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 01/08/2025] [Accepted: 02/06/2025] [Indexed: 02/09/2025]
Abstract
SIGNIFICANCE This study uncovers PDAC-specific mechanisms that dampen immune responses to viral-repeat RNA via long interspersed nuclear element 1 ORF1p. Suppression of ORF1p activates antiviral responses, reducing tumor growth and epithelial-mesenchymal transition. High ORF1p expression correlates with poor prognosis, highlighting its potential as a therapeutic target for PDAC.
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Affiliation(s)
- Eunae You
- Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts
- Department of Life Sciences, Korea University, Seoul, Republic of Korea
| | - Bidish K. Patel
- Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts
| | - Alexandra S. Rojas
- Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts
| | - Siyu Sun
- Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Natalie I. Ho
- Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts
| | - Ildiko E. Phillips
- Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts
| | - Michael J. Raabe
- Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts
| | - Yuhui Song
- Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts
| | - Katherine H. Xu
- Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts
| | - Joshua R. Kocher
- Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts
| | - Peter M. Richieri
- Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts
| | - Phoebe Shin
- Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts
| | - Martin S. Taylor
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Linda T. Nieman
- Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts
| | - Benjamin D. Greenbaum
- Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
- Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, Weill Cornell Medical College, New York, New York
| | - David T. Ting
- Mass General Cancer Center, Harvard Medical School, Charlestown, Massachusetts
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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Seidel T, Ohri N, Glaß M, Sunami Y, Müller LP, Kleeff J. Stromal Cells in Early Inflammation-Related Pancreatic Carcinogenesis-Biology and Its Potential Role in Therapeutic Targeting. Cancers (Basel) 2025; 17:1541. [PMID: 40361466 DOI: 10.3390/cancers17091541] [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: 04/03/2025] [Revised: 04/28/2025] [Accepted: 04/28/2025] [Indexed: 05/15/2025] Open
Abstract
The stroma of healthy pancreases contains various non-hematopoietic, non-endothelial mesenchymal cells. It is altered by chronic inflammation which in turn is a major contributor to the development of pancreatic adenocarcinoma (PDAC). In PDAC, the stroma plays a decisive and well-investigated role for tumor progression and therapy response. This review addresses the central role of stromal cells in the early inflammation-driven development of PDAC. It focuses on major subpopulations of pancreatic mesenchymal cells, i.e., fibroblasts, pancreatic stellate cells, and multipotent stroma cells, particularly their activation and functional alterations upon chronic inflammation including the development of different types of carcinoma-associated fibroblasts. In the second part, the current knowledge on the impact of activated stroma cells on acinar-to-ductal metaplasia and the transition to pancreatic intraepithelial neoplasia is summarized. Finally, putative strategies to target stroma cells and their signaling in early pancreatic carcinogenesis are reflected. In summary, the current data show that the activation of pancreatic stroma cells and the resulting fibrotic changes has pro- and anti-carcinogenetic effects but, overall, creates a carcinogenesis-promoting microenvironment. However, this is a dynamic process and the therapeutic targeting of specific pathways and cells requires in-depth knowledge of the molecular interplay of various cell types.
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Affiliation(s)
- Tina Seidel
- Department of Internal Medicine, University Hospital Halle, 06120 Halle (Saale), Germany
| | - Nupur Ohri
- Department of Visceral, Vascular and Endocrine Surgery, University Hospital Halle, 06120 Halle (Saale), Germany
| | - Markus Glaß
- Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany
| | - Yoshiaki Sunami
- Department of Visceral, Vascular and Endocrine Surgery, University Hospital Halle, 06120 Halle (Saale), Germany
| | - Lutz P Müller
- Department of Internal Medicine, University Hospital Halle, 06120 Halle (Saale), Germany
| | - Jörg Kleeff
- Department of Visceral, Vascular and Endocrine Surgery, University Hospital Halle, 06120 Halle (Saale), Germany
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35
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Lin Q, Guan S, Peng M, Zhang K, Zhang H, Mo T, Yu H. Comprehensive analysis of SQOR involvement in ferroptosis resistance of pancreatic ductal adenocarcinoma in hypoxic environments. Front Immunol 2025; 16:1513589. [PMID: 40375994 PMCID: PMC12078260 DOI: 10.3389/fimmu.2025.1513589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 04/07/2025] [Indexed: 05/18/2025] Open
Abstract
Introduction Pancreatic ductal adenocarcinoma (PDAC) exhibits higher hypoxia level than most solid tumors, and the presence of intratumoral hypoxia is associated with a poor prognosis. However, the identification of hypoxia levels based on pathological images, and the mechanisms regulating ferroptosis resistance, remain to be elucidated. The objective of this study was to construct a deep learning model to evaluate the hypoxia characteristics of PDAC and to explore the role of Sulfide quinone oxidoreductase (SQOR) in hypoxia-mediated ferroptosis resistance. Methods Multi-omics data were integrated to analyze the correlation between hypoxia score of PDAC, SQOR expression and prognosis, and ferroptosis resistance level. A deep learning model of Whole Slide Images (WSIs) were constructed to predict the hypoxia level of patients. In vitro hypoxia cell models, SQOR knockdown experiments and nude mouse xenograft models were used to verify the regulatory function of SQOR on ferroptosis. Results PDAC exhibited significantly higher hypoxia levels than normal tissues, correlating with reduced overall survival in patients. In slide level, our deep learning model can effectively identify PDAC hypoxia levels with good performance. SQOR was upregulated in tumor tissues and positively associated with both hypoxia score and ferroptosis resistance. SQOR promotes the malignant progression of PDAC in hypoxic environment by enhancing the resistance of tumor cells to ferroptosis. SQOR knockdown resulted in decreased cell viability, decreased migration ability and increased MDA level under hypoxic Ersatin induced conditions. Furthermore, SQOR inhibitor in combination with ferroptosis inducer has the potential to inhibit tumor growth in vivo in a synergistic manner. Discussion This study has established a hypoxia detection model of PDAC based on WSIs, providing a new tool for clinical evaluation. The study revealed a new mechanism of SQOR mediating ferroptosis resistance under hypoxia and provided a basis for targeted therapy.
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Affiliation(s)
- Quan Lin
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shiwei Guan
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Minghui Peng
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Kailun Zhang
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hewei Zhang
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Taoming Mo
- Department of Pathology, Medical School of Nantong University, Nantong, Jiangsu, China
| | - Haibo Yu
- Department of Hepatobiliary Surgery, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
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36
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Shakiba M, Tuveson DA. Macrophages and fibroblasts as regulators of the immune response in pancreatic cancer. Nat Immunol 2025; 26:678-691. [PMID: 40263612 DOI: 10.1038/s41590-025-02134-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 03/13/2025] [Indexed: 04/24/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancers that has yet to benefit from immunotherapies. This is primarily a result of its characteristic 'cold' tumor microenvironment composed of cancer-associated fibroblasts (CAFs), a dense network of extracellular matrix and several immune cell types, the most abundant of which are the tumor-associated macrophages (TAMs). Advances in single-cell and spatial technologies have elucidated the vast functional heterogeneity of CAFs and TAMs, their symbiotic relationship and their cooperative role in the tumor microenvironment. In this Review, we provide an overview of the heterogeneity of CAFs and TAMs, how they establish an immunosuppressive microenvironment and their collaboration in the remodeling of the extracellular matrix. Finally, we examine why the impact of immunotherapy in PDAC has been limited and how a detailed molecular and spatial understanding of the combined role of CAFs and TAMs is paramount to the design of effective therapies.
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Affiliation(s)
- Mojdeh Shakiba
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
- Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY, USA
| | - David A Tuveson
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
- Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY, USA.
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Nejat Dehkordi A, Maddahi M, Vafa P, Ebrahimi N, Aref AR. Salivary biomarkers: a promising approach for predicting immunotherapy response in head and neck cancers. Clin Transl Oncol 2025; 27:1887-1920. [PMID: 39377974 DOI: 10.1007/s12094-024-03742-8] [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: 06/15/2024] [Accepted: 09/21/2024] [Indexed: 04/27/2025]
Abstract
Head and neck cancers, including cancers of the mouth, throat, voice box, salivary glands, and nose, are a significant global health issue. Radiotherapy and surgery are commonly used treatments. However, due to treatment resistance and disease recurrence, new approaches such as immunotherapy are being explored. Immune checkpoint inhibitors (ICIs) have shown promise, but patient responses vary, necessitating predictive markers to guide appropriate treatment selection. This study investigates the potential of non-invasive biomarkers found in saliva, oral rinses, and tumor-derived exosomes to predict ICI response in head and neck cancer patients. The tumor microenvironment significantly impacts immunotherapy efficacy. Oral biomarkers can provide valuable information on composition, such as immune cell presence and checkpoint expression. Elevated tumor mutation load is also associated with heightened immunogenicity and ICI responsiveness. Furthermore, the oral microbiota may influence treatment outcomes. Current research aims to identify predictive salivary biomarkers. Initial studies indicate that tumor-derived exosomes and miRNAs present in saliva could identify immunosuppressive pathways and predict ICI response. While tissue-based markers like PD-L1 have limitations, combining multiple oral fluid biomarkers could create a robust panel to guide treatment decisions and advance personalized immunotherapy for head and neck cancer patients.
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Affiliation(s)
| | - Moein Maddahi
- Faculty of Density, Yeditepe University, Istanbul, Turkey
| | - Parinaz Vafa
- Faculty of Density, Yeditepe University, Istanbul, Turkey
| | - Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran.
| | - Amir Reza Aref
- Mass General Cancer Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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38
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Tao M, Liu W, Chen J, Liu R, Zou J, Yu B, Wang C, Huang M, Chen Q, Zhang Z, Chen Z, Sun H, Zhou C, Tan S, Zheng Y, Wang H. Transcriptome Landscape of Cancer-Associated Fibroblasts in Human PDAC. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2415196. [PMID: 40019403 PMCID: PMC12120754 DOI: 10.1002/advs.202415196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 01/27/2025] [Indexed: 03/01/2025]
Abstract
Cancer-associated fibroblasts (CAFs) play a crucial role in the progression of pancreatic ductal adenocarcinoma (PDAC). Here, integrated single-cell RNA sequencing analysis is utilized to comprehensively map CAFs in the human PDAC tumor microenvironment (TME). Normal fibroblasts (NFs) and nine distinct CAF subtypes are identified including newly identified CAF subtypes, CDCP1+FTL+ CAFs, transitional CAFs (tCAFs), interferon simulated genes (ISG)+ myofibroblastic CAFs (myCAFs), and proliferative CAFs (pCAFs). CDCP1+FTL+ CAFs, pCAFs, and ISG+ myCAFs are associated with unfavorable clinical outcomes. CDCP1+FTL+ CAFs exhibit enhanced glycolysis and iron metabolism, resisting ferroptosis. The antigen-presenting CAFs (apCAFs) show high heterogeneity, consisting of multiple subtypes expressing distinct immune cell signatures. The CAF subtypes display differentiation plasticity, transitioning from early normal-like CAFs (nCAFs) to inflammatory CAFs (iCAFs) and myCAFs, ultimately leading to more invasive pCAFs. AP-1 family members FOS and JUN regulate the malignant phenotype conversion of NFs to nCAFs, while transforming growth factor-β (TGFβ) and interferon-γ (IFNγ) signals trigger the interconversion between classic myCAFs and iCAFs, respectively. A close interaction between CAFs and myeloid cells (especially neutrophils) is further observed in PDAC-TME, mainly mediated by CXCR4-CXCL12 chemotaxis. This work depicts a detailed CAF map and its dynamic interconvertible shift, providing important insights for combined targeted CAFs therapy.
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Affiliation(s)
- Mengyu Tao
- Department of OncologyShanghai General HospitalShanghai Jiaotong University School of MedicineShanghai200800P. R. China
| | - Wenting Liu
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Jianhua Chen
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Rujiao Liu
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Jianling Zou
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Bo Yu
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Chenchen Wang
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Mingzhu Huang
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Qingjian Chen
- Department of OncologyShanghai General HospitalShanghai Jiaotong University School of MedicineShanghai200800P. R. China
| | - Zhe Zhang
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Zhiyu Chen
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
| | - Haoyu Sun
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
- Department of ImmunologySchool of Basic Medical SciencesFudan UniversityShanghai200032China
| | - Cheng Zhou
- Department of Radiation OncologyNanfang HospitalSouthern Medical UniversityGuangzhou510515P. R. China
| | - Shuguang Tan
- The Second Affiliated HospitalZhejiang University School of MedicineHangzhou310009China
| | - Yuxuan Zheng
- Human Phenome InstituteMinhang HosptialFudan UniversityShanghai201203P. R. China
| | - Hongxia Wang
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghai200032P. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032P. R. China
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Gao L, Lv G, Liu Z, Tian Y, Han F, Li L, Wang G, Zhang Y. Alcohol-induced C/EBP β-driven VIRMA decreases oxidative stress and promotes pancreatic ductal adenocarcinoma growth and metastasis via the m6A/YTHDF2/SLC43A2 pathway. Oncogene 2025; 44:1118-1132. [PMID: 39900725 DOI: 10.1038/s41388-025-03283-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 01/06/2025] [Accepted: 01/22/2025] [Indexed: 02/05/2025]
Abstract
N6-methyladenosine (m6A) plays a role in the development of tumors. However, the specific role of VIRMA, an RNA methyltransferase, in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study shows that VIRMA expression is elevated in PDAC. Increased VIRMA levels promoted PDAC growth and spread, while reducing VIRMA expression slowed these processes. VIRMA facilitated SLC43A2 mRNA degradation through an m6A-YTHDF2 pathway. The resulting decrease in SLC43A2 reduced phenylalanine absorption and oxidative stress, further driving PDAC progression. Furthermore, alcohol increased C/EBP β expression, which bound to VIRMA's promoter, enhancing its transcription. These findings suggest a connection between alcohol consumption, m6A modifications, and phenylalanine absorption in PDAC progression, offering a new approach to combat this disease.
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Affiliation(s)
- Lei Gao
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
- Department of Oncology and Laparoscopy Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Gaoyuan Lv
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ziying Liu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yitong Tian
- Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Fang Han
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Le Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Gang Wang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
- Department of Oncology and Laparoscopy Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Yuhua Zhang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.
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40
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Romoli J, Chiodelli P, Signoroni PB, Vertua E, Ferrari C, Giuzzi E, Paini A, Scalvini E, Papait A, Stefani FR, Silini AR, Parolini O. Modeling Stromal Cells Inside the Tumor Microenvironment of Ovarian Cancer: In Vitro Generation of Cancer-Associated Fibroblast-Like Cells and Their Impact in a 3D Model. MedComm (Beijing) 2025; 6:e70172. [PMID: 40255916 PMCID: PMC12006666 DOI: 10.1002/mco2.70172] [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: 04/24/2024] [Revised: 01/31/2025] [Accepted: 02/13/2025] [Indexed: 04/22/2025] Open
Abstract
The tumor microenvironment (TME) is the combination of cells and factors that promotes tumor progression, and cancer-associated fibroblasts (CAFs) are a key component within TME. CAF originates from various stromal cells and is activated by factors such as transforming growth factor-beta (TGF-β) secreted by tumor cells, favoring chemoresistance and metastasis. Recent publications have underlined plasticity and heterogeneity and their strong contribution to the reactive stroma within the TME. Our study aimed to replicate the TME's structure by creating a 3D in vitro model of ovarian cancer (OC). By incorporating diverse tumor and stromal cells, we simulated a physiologically relevant environment for studying CAF-like cell behavior within tumor spheroids in a context-dependent manner. CAF-like cells were generated by exposing human dermal fibroblasts to OC cell line conditioned media in the presence or absence of TGF-β. Herein, we found that different stimuli induce the generation of heterogeneous populations of CAF-like cells. Notably, we observed the ability of CAF-like cells to shape the intratumoral architecture and to contribute to functional changes in tumor cell behavior. This study highlights the importance of precise assessment of CAF for potential therapeutic interventions and further provides a reliable model for investigating novel therapeutic targets in OC.
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Affiliation(s)
- Jacopo Romoli
- Department of Life Science and Public HealthUniversità Cattolica del Sacro CuoreRomeItaly
| | - Paola Chiodelli
- Department of Life Science and Public HealthUniversità Cattolica del Sacro CuoreRomeItaly
| | | | - Elsa Vertua
- Centro di Ricerca E. MenniFondazione Poliambulanza Istituto OspedalieroBresciaItaly
| | - Clarissa Ferrari
- Research and Clinical Trials UnitFondazione Poliambulanza Istituto OspedalieroBresciaItaly
| | - Elisabetta Giuzzi
- Centro di Ricerca E. MenniFondazione Poliambulanza Istituto OspedalieroBresciaItaly
| | - Alice Paini
- Centro di Ricerca E. MenniFondazione Poliambulanza Istituto OspedalieroBresciaItaly
| | - Elisa Scalvini
- Centro di Ricerca E. MenniFondazione Poliambulanza Istituto OspedalieroBresciaItaly
| | - Andrea Papait
- Department of Life Science and Public HealthUniversità Cattolica del Sacro CuoreRomeItaly
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCSRomeItaly
| | | | | | - Ornella Parolini
- Department of Life Science and Public HealthUniversità Cattolica del Sacro CuoreRomeItaly
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCSRomeItaly
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41
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Xu W, Yang H, Yao F. Single-cell analysis and machine learning-based integration develop an immune-responsive signature of antigen-presenting cancer-associated fibroblasts in lung adenocarcinoma. J Thorac Dis 2025; 17:2321-2338. [PMID: 40400942 PMCID: PMC12090188 DOI: 10.21037/jtd-2024-2015] [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: 11/21/2024] [Accepted: 02/18/2025] [Indexed: 05/23/2025]
Abstract
Background Cancer-associated fibroblasts (CAFs) are pivotal regulators of the tumor immune microenvironment, shaping immune responses and influencing therapeutic outcomes. While previous studies have predominantly focused on CAF subpopulations that impair responses to immune checkpoint inhibitors (ICIs), CAF subsets associated with favorable ICIs responses in lung adenocarcinoma (LUAD) remain underexplored. In this study, we integrated bulk RNA and single-cell RNA sequencing data from LUAD samples to identify CAF subpopulations relevant to ICIs efficacy. Methods Using a machine learning-driven approach, we developed a robust immune response signature based on this antigen-presenting CAFs (apCAFs) subset to predict ICIs responses. Results We uncovered a novel subset of apCAFs exhibiting macrophage-like features, characterized by the expression of major histocompatibility complex (MHC) class II, CD74, and costimulatory molecules (CD80, CD86, CD83, and CD40). This subset, distinct from classic apCAFs described in other cancer types, is strongly associated with favorable ICIs responses across multiple datasets. Notably, these macrophage-like apCAFs are present in LUAD samples prior to treatment, although their abundance varies among individuals. Patients classified as high-risk using signature calculated by a machine learning-driven approach exhibited lower overall survival rates and diminished immune cell infiltration following ICIs therapy. Conclusions Collectively, our findings establish a critical link between macrophage-like apCAFs and ICIs efficacy, offering a clinically applicable signature for patient stratification and guiding therapeutic strategies targeting the tumor microenvironment.
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Affiliation(s)
- Weijiao Xu
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haitang Yang
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feng Yao
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Thoracic Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, China
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42
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Gao F, Lu Y, Zhao Y, Zhang H. scRNA-seq reveals chemotherapy-induced tumor microenvironment changes in pancreatic ductal adenocarcinoma. Transl Cancer Res 2025; 14:2395-2409. [PMID: 40386264 PMCID: PMC12079211 DOI: 10.21037/tcr-2025-103] [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: 01/12/2025] [Accepted: 03/12/2025] [Indexed: 05/20/2025]
Abstract
Background Challenges have arisen in finding an effective treatment for pancreatic ductal adenocarcinoma (PDAC). Poor outcomes have fueled ongoing efforts to exploit the tumor microenvironment (TME) in the treatment of PDAC; however, to date, treatment strategies have largely failed. Thus, a comprehensive and deep understanding of the PDAC TME is necessary. The purpose of the present study was to investigate chemotherapy-induced tumor microenvironment changes and to optimize the response to immunotherapy in PDAC. Methods We analyzed publicly available single-cell RNA sequencing (scRNA-seq) PDAC (with or without standard chemotherapy) data and performed systematic analyses to elucidate novel mechanisms and to determinate the marker expression alteration induced by the chemotherapy. Results Lysozyme (LYZ), which is usually used as a myeloid marker, was significantly increased in the tumor cells, including myeloid cells responding to chemotherapy. Additionally, chemotherapy altered the mechanism of antigen presentation and modulated the TME, which may lead to tumor drug resistance and recurrence. Chemotherapy also affected the receptor of polio virus receptor (PVR) signaling, which shifted from TIGIT in T cells to CD226 in myeloid cells. Thus, PVR (rather than TIGIT) should be the target for treatment. Conclusions We described the characteristics of widely expressed markers in different cell types in PDAC. Chemotherapy disrupted the TME balance, altered tumor antigen presentation, and changed PVR signaling. Combining the appropriate chemical and immune therapies could improve the immune therapy response in PDAC.
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Affiliation(s)
- Fei Gao
- National Institutes for Food and Drug Control, Beijing, China
| | - Yuxiong Lu
- MyGene Diagnostics Co., Ltd., Guangzhou, China
- Guangdong Engineering Technology Research Center of Multiplex PCR & Tumor Diagnostics, Guangzhou, China
| | - Yanyan Zhao
- MyGene Diagnostics Co., Ltd., Guangzhou, China
- Guangdong Engineering Technology Research Center of Multiplex PCR & Tumor Diagnostics, Guangzhou, China
| | - Hua Zhang
- Precision Medicine Center, Jilin City Central Hospital, Jilin, China
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Finger AM, Hendley AM, Figueroa D, Gonzalez H, Weaver VM. Tissue mechanics in tumor heterogeneity and aggression. Trends Cancer 2025:S2405-8033(25)00096-2. [PMID: 40307158 DOI: 10.1016/j.trecan.2025.04.004] [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: 08/27/2024] [Revised: 03/10/2025] [Accepted: 04/04/2025] [Indexed: 05/02/2025]
Abstract
Tumorigenesis ensues within a heterogeneous tissue microenvironment that promotes malignant transformation, metastasis and treatment resistance. A major feature of the tumor microenvironment is the heterogeneous population of cancer-associated fibroblasts and myeloid cells that stiffen the extracellular matrix. The heterogeneously stiffened extracellular matrix in turn activates cellular mechanotransduction and creates a hypoxic and metabolically hostile microenvironment. The stiffened extracellular matrix and elevated mechanosignaling also drive tumor aggression by fostering tumor cell growth, survival, and invasion, compromising antitumor immunity, expanding cancer stem cell frequency, and increasing mutational burden, which promote intratumor heterogeneity. Delineating the molecular mechanisms whereby tissue mechanics regulate these phenotypes should help to clarify the basis for tumor heterogeneity and cancer aggression and identify novel therapeutic targets that could improve patient outcome. Here, we discuss the role of the extracellular matrix in driving cancer aggression through its impact on tumor heterogeneity.
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Affiliation(s)
- Anna-Marie Finger
- Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA 94143; Current address: Liver Disease Research, Global Drug Discovery, Novo Nordisk A/S, Malov, Denmark
| | - Audrey Marie Hendley
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA 94143
| | - Diego Figueroa
- Department of Radiation Oncology, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA
| | - Hugo Gonzalez
- Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA 94143; Current address: Laboratory of Tumor Microenvironment and Metastasis, Centro Ciencia & Vida, Santiago, Chile
| | - Valerie Marie Weaver
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA 94143; Department of Radiation Oncology, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA.
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Pei G, Min J, Rajapakshe KI, Branchi V, Liu Y, Selvanesan BC, Thege F, Sadeghian D, Zhang D, Cho KS, Chu Y, Dai E, Han G, Li M, Yee C, Takahashi K, Garg B, Tiriac H, Bernard V, Semaan A, Grem JL, Caffrey TC, Burks JK, Lowy AM, Aguirre AJ, Grandgenett PM, Hollingsworth MA, Guerrero PA, Wang L, Maitra A. Spatial mapping of transcriptomic plasticity in metastatic pancreatic cancer. Nature 2025:10.1038/s41586-025-08927-x. [PMID: 40269162 DOI: 10.1038/s41586-025-08927-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 03/20/2025] [Indexed: 04/25/2025]
Abstract
Patients with treatment-refractory pancreatic cancer often succumb to systemic metastases1-3; however, the transcriptomic heterogeneity that underlies therapeutic recalcitrance remains understudied, particularly in a spatial context. Here we construct high-resolution maps of lineage states, clonal architecture and the tumour microenvironment (TME) using spatially resolved transcriptomics from 55 samples of primary tumour and metastases (liver, lung and peritoneum) collected from rapid autopsies of 13 people. We observe discernible transcriptomic shifts in cancer-cell lineage states as tumours transition from primary sites to organ-specific metastases, with the most pronounced intra-patient distinctions between liver and lung. Phylogenetic trees constructed from inferred copy number variations in primary and metastatic loci in each patient highlight diverse patient-specific evolutionary trajectories and clonal dissemination. We show that multiple tumour lineage states co-exist in each tissue, including concurrent metastatic foci in the same organ. Agnostic to tissue site, lineage states correlate with distinct TME features, such as the spatial proximity of TGFB1-expressing myofibroblastic cancer-associated fibroblasts (myCAFs) to aggressive 'basal-like' cancer cells, but not to cells in the 'classical' or 'intermediate' states. These findings were validated through orthogonal and cross-species analyses using mouse tissues and patient-derived organoids. Notably, basal-like cancer cells aligned with myCAFs correlate with plasma-cell exclusion from the tumour milieu, and neighbouring cell analyses suggest that CXCR4-CXCL12 signalling is the underlying basis for observed immune exclusion. Collectively, our findings underscore the profound transcriptomic heterogeneity and microenvironmental dynamics that characterize treatment-refractory pancreatic cancer.
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Affiliation(s)
- Guangsheng Pei
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jimin Min
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kimal I Rajapakshe
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vittorio Branchi
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yunhe Liu
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Benson Chellakkan Selvanesan
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Fredrik Thege
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dorsay Sadeghian
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Daiwei Zhang
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
| | - Kyung Serk Cho
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yanshuo Chu
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Enyu Dai
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Guangchun Han
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mingyao Li
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Cassian Yee
- Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kazuki Takahashi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Bharti Garg
- Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Herve Tiriac
- Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Vincent Bernard
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Alexander Semaan
- Department of Surgery, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Jean L Grem
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Thomas C Caffrey
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Jared K Burks
- Department of Leukemia and Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Andrew M Lowy
- Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Andrew J Aguirre
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Paul M Grandgenett
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Michael A Hollingsworth
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Paola A Guerrero
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Linghua Wang
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
- James P. Allison Institute, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Institute for Data Science in Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Anirban Maitra
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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45
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Weber F, Reese KL, Pantel K, Smit DJ. Cancer-associated fibroblasts as a potential novel liquid biopsy marker in cancer patients. J Exp Clin Cancer Res 2025; 44:127. [PMID: 40259388 PMCID: PMC12010557 DOI: 10.1186/s13046-025-03387-7] [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: 01/14/2025] [Accepted: 04/07/2025] [Indexed: 04/23/2025] Open
Abstract
Cancer-associated fibroblasts (CAFs) are tissue residing cells within the tumor microenvironment (TME). Stromal CAFs have been shown to be associated with poor prognosis and tumor progression in several solid tumor entities. Although the molecular mechanisms are not fully understood yet, a critical role within the TME through direct interaction with the tumor cells as well as other cells has been proposed. While most studies on CAFs focus on stromal CAFs, recent reports highlight the possibility of detecting circulating CAFs (cCAFs) in the blood. In contrast to invasive tissue biopsies for stromal CAF characterization, liquid biopsy allows a minimally invasive isolation of cCAFs. Furthermore, liquid biopsy methods could enable continuous monitoring of cCAFs in cancer patients and therefore may present a novel biomarker for solid tumors. In this work, we present an overview of cCAF studies currently available and summarize the liquid biopsy techniques for cCAF isolation and detection. Moreover, the future research directions in the emerging field are highlighted and the potential applications of cCAFs as novel biomarkers for solid tumor patients discussed.
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Affiliation(s)
- Franziska Weber
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - Kim-Lea Reese
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - Klaus Pantel
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
- European Liquid Biopsy Society (ELBS), Martinistraße 52, 20246, Hamburg, Germany
| | - Daniel J Smit
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
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46
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FENG LIWEN, CHEN YUTING, JIN WENYI. Research progress on cancer-associated fibroblasts in osteosarcoma. Oncol Res 2025; 33:1091-1103. [PMID: 40296919 PMCID: PMC12033999 DOI: 10.32604/or.2024.054207] [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: 05/21/2024] [Accepted: 08/26/2024] [Indexed: 04/30/2025] Open
Abstract
Osteosarcoma (OS) is a prevalent primary bone malignancy with limited treatment options. Therefore, it is imperative to investigate and understand the mechanisms underlying OS pathogenesis. Cancer-associated fibroblasts (CAFs) are markedly abundant in tumor stromal cells and are essentially involved in the modulation of tumor occurrence and development. In recent years, CAFs have become a hotspot as researchers aim to elucidate CAF mechanisms that regulate tumor progression. However, most studies on CAFs are limited to a few common cancers, and their association with OS remains elusive. This review describes the role and current knowledge of CAFs in OS, focusing on their potential cellular origin, classification, and diverse functionality. It was found that CAFs influenced OS tumor cell signaling, proliferation, invasion, metastasis, epithelial-mesenchymal transition, stemness maintenance, angiogenesis, and the ability to modify immune system components. Furthermore, findings on other common cancers indicated that effective therapeutic strategies included the manipulation of CAF activation, targeting CAF-derived components, and depletion of CAFs by biomarkers. This review provides new insights and a theoretical basis for OS research.
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Affiliation(s)
- LIWEN FENG
- Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - YUTING CHEN
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - WENYI JIN
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, 430022, China
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47
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Zhang H, Zhuang Z, Hong L, Wang R, Xu J, Tang Y. The malignant signature gene of cancer-associated fibroblasts serves as a potential prognostic biomarker for colon adenocarcinoma patients. Front Immunol 2025; 16:1589678. [PMID: 40313961 PMCID: PMC12043632 DOI: 10.3389/fimmu.2025.1589678] [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: 03/07/2025] [Accepted: 04/01/2025] [Indexed: 05/03/2025] Open
Abstract
Background Colon adenocarcinoma (COAD) is the most frequently occurring type of colon cancer. Cancer-associated fibroblasts (CAFs) are pivotal in facilitating tumor growth and metastasis; however, their specific role in COAD is not yet fully understood. This research utilizes single-cell RNA sequencing (scRNA-seq) to identify and validate gene markers linked to the malignancy of CAFs. Methods ScRNA-seq data was downloaded from a database and subjected to quality control, dimensionality reduction, clustering, cell annotation, cell communication analysis, and enrichment analysis, specifically focusing on fibroblasts in tumor tissues compared to normal tissues. Fibroblast subsets were isolated, dimensionally reduced, and clustered, then combined with copy number variation (CNV) inference and pseudotime trajectory analysis to identify genes related to malignancy. A Cox regression model was constructed based on these genes, incorporating LASSO analysis, nomogram construction, and validation.Subsequently, we established two FNDC5-knockdown cell lines and utilized colony formation and transwell assays to investigate the impact of FNDC5 on cellular biological behaviors. Results Using scRNA-seq data, we analyzed 8,911 cells from normal and tumor samples, identifying six distinct cell types. Cell communication analysis highlighted interactions between these cell types mediated by ligands and receptors. CNV analysis classified CAFs into three groups based on malignancy levels. Pseudo-time analysis identified 622 pseudotime-related genes and generated a forest plot using univariate Cox regression. Lasso regression identified the independent prognostic gene FNDC5, which was visualized in a nomogram. Kaplan-Meier survival analysis confirmed the prognostic value of FNDC5, showing associations with T stage and distant metastasis. In vitro experiment results demonstrated a strong association between FNDC5 expression levels and the proliferative, migratory, and invasive abilities of colon cancer cells. Conclusion We developed a risk model for genes related to the malignancy of CAFs and identified FNDC5 as a potential therapeutic target for COAD.
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Affiliation(s)
| | | | | | | | | | - Youyuan Tang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
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48
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Lan X, Li W, Zhao K, Wang J, Li S, Zhao H. Revisiting the role of cancer-associated fibroblasts in tumor microenvironment. Front Immunol 2025; 16:1582532. [PMID: 40313969 PMCID: PMC12043473 DOI: 10.3389/fimmu.2025.1582532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Accepted: 03/31/2025] [Indexed: 05/03/2025] Open
Abstract
Cancer-associated fibroblasts (CAFs) are integral components of the tumor microenvironment playing key roles in tumor progression, metastasis, and therapeutic resistance. However, challenges persist in understanding their heterogeneity, origin, and functional diversity. One major obstacle is the lack of standardized naming conventions for CAF subpopulations, with current systems failing to capture their full complexity. Additionally, the identification of CAFs is hindered by the absence of specific biomarkers, limiting the precision of diagnostic and therapeutic strategies. In vitro culture conditions often fail to maintain the in vivo characteristics of CAFs, which complicates their study and the translation of findings to clinical practice. Although current detection methods, such as antibodies, mRNA probes, and single-cell transcriptomics, offer insights into CAF biology, they lack standardization and fail to provide reliable quantitative measures. Furthermore, the dynamic interactions between CAFs, tumor cells, and immune cells within the TME remain insufficiently understood, and the role of CAFs in immune evasion and therapy resistance is an area of ongoing research. Understanding how CAFs influence drug resistance and the immune response is essential for developing more effective cancer therapies. This review aims to provide an in-depth analysis of the challenges in CAF research, propose future research directions, and emphasize the need for improved CAF-targeted therapeutic strategies. By addressing these gaps, it seeks to highlight the potential of CAFs as targets for overcoming therapeutic resistance and enhancing the efficacy of cancer treatments.
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Affiliation(s)
| | | | | | | | | | - Hai Zhao
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
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49
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Lloyd EG, Jihad M, Manansala JS, Li W, Cheng PS, Mucciolo G, Zaccaria M, Teles SP, Henríquez JA, Harish S, Brais R, Ashworth S, Luo W, Johnson PM, Veghini L, Vallespinos M, Corbo V, Biffi G. SMAD4 and KRAS Status Shapes Cancer Cell-Stromal Cross-Talk and Therapeutic Response in Pancreatic Cancer. Cancer Res 2025; 85:1368-1389. [PMID: 39841099 PMCID: PMC7617379 DOI: 10.1158/0008-5472.can-24-2330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 12/09/2024] [Accepted: 01/08/2025] [Indexed: 01/23/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) contains an extensive stroma that modulates response to therapy, contributing to the dismal prognosis associated with this cancer. Evidence suggests that PDAC stromal composition is shaped by mutations within malignant cells, but most previous work has focused on preclinical models driven by KrasG12D and mutant Trp53. Elucidation of the contribution of additional known oncogenic drivers, including KrasG12V mutation and Smad4 loss, is needed to increase the understanding of malignant cell-stromal cell cross-talk in PDAC. In this study, we used single-cell RNA sequencing to analyze the cellular landscape of Trp53-mutant mouse models driven by KrasG12D or KrasG12V, in which Smad4 was wild type or deleted. KrasG12DSmad4-deleted PDAC developed a fibro-inflammatory rich stroma with increased malignant JAK/STAT cell signaling and enhanced therapeutic response to JAK/STAT inhibition. SMAD4 loss in KrasG12V PDAC differently altered the tumor microenvironment compared with KrasG12D PDAC, and the malignant compartment lacked JAK/STAT signaling dependency. Thus, malignant cell genotype affects cancer cell and stromal cell phenotypes in PDAC, directly affecting therapeutic efficacy. Significance: SMAD4 loss differentially impacts malignant cell-stromal cell signaling and treatment sensitivity of pancreatic tumors driven by KRASG12D or KRASG12V, highlighting the importance of understanding genotype-phenotype relationships for precision therapy.
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Affiliation(s)
- Eloise G. Lloyd
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson way, CB2 0RE, Cambridge, UK
| | - Muntadher Jihad
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson way, CB2 0RE, Cambridge, UK
| | - Judhell S. Manansala
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson way, CB2 0RE, Cambridge, UK
| | - Wenlong Li
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson way, CB2 0RE, Cambridge, UK
| | - Priscilla S.W. Cheng
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson way, CB2 0RE, Cambridge, UK
| | - Gianluca Mucciolo
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson way, CB2 0RE, Cambridge, UK
| | - Marta Zaccaria
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson way, CB2 0RE, Cambridge, UK
| | - Sara Pinto Teles
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson way, CB2 0RE, Cambridge, UK
| | - Joaquín Araos Henríquez
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson way, CB2 0RE, Cambridge, UK
| | - Sneha Harish
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson way, CB2 0RE, Cambridge, UK
| | - Rebecca Brais
- Histopathology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK
| | - Sally Ashworth
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson way, CB2 0RE, Cambridge, UK
| | - Weike Luo
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson way, CB2 0RE, Cambridge, UK
| | - Paul M. Johnson
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson way, CB2 0RE, Cambridge, UK
| | - Lisa Veghini
- Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy
| | - Mireia Vallespinos
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson way, CB2 0RE, Cambridge, UK
| | - Vincenzo Corbo
- Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy
- ARC-Net Research Centre, University of Verona, Verona, Italy
| | - Giulia Biffi
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson way, CB2 0RE, Cambridge, UK
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50
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Mohammad SI, Vasudevan A, Hussein Alzewmel A, Rab SO, Ballal S, Kalia R, Bethanney Janney J, Ray S, Joshi KK, Yasin HA. The mutual effects of stearoyl-CoA desaturase and cancer-associated fibroblasts: A focus on cancer biology. Exp Cell Res 2025; 447:114508. [PMID: 40122505 DOI: 10.1016/j.yexcr.2025.114508] [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: 01/25/2025] [Revised: 03/06/2025] [Accepted: 03/06/2025] [Indexed: 03/25/2025]
Abstract
The tumor microenvironment (TME) 's primary constituents that promote cancer development are cancer-associated fibroblasts (CAFs). Metabolic remodeling has been shown to control CAF activity, particularly aberrant lipid metabolism. SCD1 can be thought of as the primary enzyme controlling the fluidity of lipid bilayers by gradually converting saturated fatty acids into monounsaturated fatty acids. Furthermore, its crucial function in the onset and spread of cancer is well acknowledged. Even with the increasing amount of research on changes in lipid metabolism, this problem remains a relatively understudied aspect of cancer research. Blocking several fatty acid synthesis-related enzymes highly expressed in cancerous cells inhibits cell division and encourages apoptosis. This is the situation with SCD1, whose overexpression has been linked to several changed tumors and cells. Both genetic and pharmacological silencing of SCD1 in cancer cells prevents glucose-mediated lipogenesis and tumor cell growth. However, its role in CAFs, hence, cancer biology, has been less studied. This study aimed to review the role of SCD1 in CAF biology, shedding light on their function in cancer cell biology.
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Affiliation(s)
- Suleiman Ibrahim Mohammad
- Research Follower, INTI International University, 71800 Negeri Sembilan, Malaysia; Electronic Marketing and Social Media, Economic and Administrative Sciences, Zarqa University, Jordan.
| | - Asokan Vasudevan
- Faculty of Business and Communications, INTI International University, 71800, Negeri Sembilan, Malaysia.
| | - Ahmad Hussein Alzewmel
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University, Najaf, Iraq; Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University of Babylon, Babylon, Iraq
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Rishiv Kalia
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - J Bethanney Janney
- Department of Biomedical, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Subhashree Ray
- Department of Biochemistry, IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to be University), Bhubaneswar, Odisha, 751003, India
| | - Kamal Kant Joshi
- Department of Allied Science, Graphic Era Hill University, Dehradun, India; Graphic Era Deemed to be University, Dehradun, Uttarakhand, India
| | - Hatif Abdulrazaq Yasin
- Department of Medical Laboratories Technology, Al-Nisour University College, Nisour Seq. Karkh, Baghdad, Iraq
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