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Zhang J, Yin R, Xue Y, Qin R, Wang X, Wu S, Zhu J, Li YS, Zhang C, Wei Y. Advances in the study of epithelial mesenchymal transition in cancer progression: Role of miRNAs. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2025; 196:69-90. [PMID: 40185337 DOI: 10.1016/j.pbiomolbio.2025.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 04/02/2025] [Accepted: 04/02/2025] [Indexed: 04/07/2025]
Abstract
Epithelial-mesenchymal transition (EMT) has been extensively studied for its roles in tumor metastasis, the generation and maintenance of cancer stem cells and treatment resistance. Epithelial mesenchymal plasticity allows cells to switch between various states within the epithelial-mesenchymal spectrum, resulting in a mixed epithelial/mesenchymal phenotypic profile. This plasticity underlies the acquisition of multiple malignant features during cancer progression and poses challenges for EMT in tumors. MicroRNAs (miRNAs) in the microenvironment affect numerous signaling processes through diverse mechanisms, influencing physiological activities. This paper reviews recent advances in EMT, the role of different hybrid states in tumor progression, and the important role of miRNAs in EMT. Furthermore, it explores the relationship between miRNA-based EMT therapies and their implications for clinical practice, discussing how ongoing developments may enhance therapeutic outcomes.
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Affiliation(s)
- Jia Zhang
- School of Pharmacy, Jiangsu University, Zhen Jiang, 212013, China
| | - Runting Yin
- School of Pharmacy, Jiangsu University, Zhen Jiang, 212013, China.
| | - Yongwang Xue
- School of Pharmacy, Jiangsu University, Zhen Jiang, 212013, China
| | - Rong Qin
- Department of Medical Oncology, Jiangsu University Affiliated People's Hospital, Zhenjiang Clinical Medical College of Nanjing Medical University, Zhenjiang, China
| | - Xuequan Wang
- Department of Radiation Oncology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Shuming Wu
- School of Pharmacy, Jiangsu University, Zhen Jiang, 212013, China
| | - Jun Zhu
- School of Pharmacy, Jiangsu University, Zhen Jiang, 212013, China
| | - Yan-Shuang Li
- Department of Breast Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Cai Zhang
- School of Pharmacy, Jiangsu University, Zhen Jiang, 212013, China
| | - Yuan Wei
- School of Pharmacy, Jiangsu University, Zhen Jiang, 212013, China.
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Sehgal M, Nayak SP, Sahoo S, Somarelli JA, Jolly MK. Mutually exclusive teams-like patterns of gene regulation characterize phenotypic heterogeneity along the noradrenergic-mesenchymal axis in neuroblastoma. Cancer Biol Ther 2024; 25:2301802. [PMID: 38230570 PMCID: PMC10795782 DOI: 10.1080/15384047.2024.2301802] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 01/01/2024] [Indexed: 01/18/2024] Open
Abstract
Neuroblastoma is the most frequent extracranial pediatric tumor and leads to 15% of all cancer-related deaths in children. Tumor relapse and therapy resistance in neuroblastoma are driven by phenotypic plasticity and heterogeneity between noradrenergic (NOR) and mesenchymal (MES) cell states. Despite the importance of this phenotypic plasticity, the dynamics and molecular patterns associated with these bidirectional cell-state transitions remain relatively poorly understood. Here, we analyze multiple RNA-seq datasets at both bulk and single-cell resolution, to understand the association between NOR- and MES-specific factors. We observed that NOR-specific and MES-specific expression patterns are largely mutually exclusive, exhibiting a "teams-like" behavior among the genes involved, reminiscent of our earlier observations in lung cancer and melanoma. This antagonism between NOR and MES phenotypes was also associated with metabolic reprogramming and with immunotherapy targets PD-L1 and GD2 as well as with experimental perturbations driving the NOR-MES and/or MES-NOR transition. Further, these "teams-like" patterns were seen only among the NOR- and MES-specific genes, but not in housekeeping genes, possibly highlighting a hallmark of network topology enabling cancer cell plasticity.
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Affiliation(s)
- Manas Sehgal
- Department of Bioengineering, Indian Institute of Science, Bangalore, India
| | - Sonali Priyadarshini Nayak
- Department of Bioengineering, Indian Institute of Science, Bangalore, India
- Max Planck School Matter to Life, University of Göttingen, Göttingen, Germany
| | - Sarthak Sahoo
- Department of Bioengineering, Indian Institute of Science, Bangalore, India
| | | | - Mohit Kumar Jolly
- Department of Bioengineering, Indian Institute of Science, Bangalore, India
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Wang K, Tao L, Zhu M, Yu X, Lu Y, Yuan B, Hu F. Melittin Inhibits Colorectal Cancer Growth and Metastasis by Ac-Tivating the Mitochondrial Apoptotic Pathway and Suppressing Epithelial-Mesenchymal Transition and Angiogenesis. Int J Mol Sci 2024; 25:11686. [PMID: 39519238 PMCID: PMC11546240 DOI: 10.3390/ijms252111686] [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: 10/18/2024] [Revised: 10/27/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
Melittin has previously been found to have a positive effect on colorectal cancer (CRC) treatment, one of the most difficult-to-treat malignancies, but the mechanism by which this effect occurs remains unclear. We evaluated melittin's pro-apoptotic and anti-metastatic effects on CRC in vitro and in vivo. The results showed that melittin-induced mitochondrial ROS bursts decreased ΔΨm, inhibited Bcl-2 expression, and increased Bax expression in both cells and tumor tissues. This led to increased mitochondrial membrane permeability and the release of pro-apoptotic factors, particularly the high expression of Cytochrome C, initiating the apoptosis program. Additionally, through wound-healing and transwell assays, melittin inhibited the migration and invasion of CRC cells. In vivo, the anti-metastatic effect of melittin was also verified in a lung metastasis mouse model. Western blotting and immunohistochemistry analysis indicated that melittin suppressed the expression of MMPs and regulated the expression of crucial EMT markers and related transcription factors, thereby inhibiting EMT. Furthermore, the melittin disrupts neovascularization, ultimately inhibiting the metastasis of CRC. In conclusion, melittin exerts anti-CRC effects by promoting apoptosis and inhibiting metastasis, providing a theoretical basis for further research on melittin as a targeted therapeutic agent for CRC.
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Affiliation(s)
| | | | | | | | | | | | - Fuliang Hu
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; (K.W.); (L.T.); (M.Z.); (X.Y.); (Y.L.); (B.Y.)
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Ban Y, Zou Y, Liu Y, Lee S, Bednarczyk RB, Sheng J, Cao Y, Wong STC, Gao D. Targeting ribosome biogenesis as a novel therapeutic approach to overcome EMT-related chemoresistance in breast cancer. eLife 2024; 12:RP89486. [PMID: 39259576 PMCID: PMC11390108 DOI: 10.7554/elife.89486] [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] [Indexed: 09/13/2024] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) contributes significantly to chemotherapy resistance and remains a critical challenge in treating advanced breast cancer. The complexity of EMT, involving redundant pro-EMT signaling pathways and its paradox reversal process, mesenchymal-to-epithelial transition (MET), has hindered the development of effective treatments. In this study, we utilized a Tri-PyMT EMT lineage-tracing model in mice and single-cell RNA sequencing (scRNA-seq) to comprehensively analyze the EMT status of tumor cells. Our findings revealed elevated ribosome biogenesis (RiBi) during the transitioning phases of both EMT and MET processes. RiBi and its subsequent nascent protein synthesis mediated by ERK and mTOR signalings are essential for EMT/MET completion. Importantly, inhibiting excessive RiBi genetically or pharmacologically impaired the EMT/MET capability of tumor cells. Combining RiBi inhibition with chemotherapy drugs synergistically reduced metastatic outgrowth of epithelial and mesenchymal tumor cells under chemotherapies. Our study suggests that targeting the RiBi pathway presents a promising strategy for treating patients with advanced breast cancer.
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Affiliation(s)
- Yi Ban
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, United States
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, United States
| | - Yue Zou
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, United States
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, United States
| | - Yingzhuo Liu
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, United States
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, United States
| | - Sharrel Lee
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, United States
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, United States
- Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, United States
| | - Robert B Bednarczyk
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, United States
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, United States
| | - Jianting Sheng
- Systems Medicine and Bioengineering Department, Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, United States
| | - Yuliang Cao
- Systems Medicine and Bioengineering Department, Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, United States
| | - Stephen T C Wong
- Systems Medicine and Bioengineering Department, Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, United States
- Department of Radiology, Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, United States
- Department of Pathology and Laboratory Medicine, Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, United States
| | - Dingcheng Gao
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, United States
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, United States
- Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, United States
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, United States
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Dong X, Xue S, Chen C, Jiang Z, Wu X, Wang W. MYCT-1 Gene Expression in Patients with Gastric Cancer: an Ex Vivo Study. Appl Biochem Biotechnol 2024; 196:5114-5126. [PMID: 38112991 DOI: 10.1007/s12010-023-04754-w] [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] [Accepted: 10/17/2023] [Indexed: 12/21/2023]
Abstract
Ploidy, p53, bcl-2, and c-myc genes are associated with gastric cancer. Myc target 1 (MYCT1) gene is an oncogenic gene and is associated with cancer progression through different signal transduction pathways identifying the corresponding genes The objective of the study was to evaluate the association between MYCT1 gene expression and gastric cancer. Real-time polymerase chain reaction (RT-PCR), western blot analysis, cell growth study, and TUNEL assay were performed for the human gastric cancer cell lines and human embryonic kidney cell line. β-Actin gene preferred as a control in RT-PCR. The ratio of MYCT1 gene expression to β-actin gene expression less than 0.5 was considered as downregulation. Using SDS-PAGE MYCT1 gene expression was measured in western blot analysis. Cells with and without the MYCT1 gene were incubated in 35 mm plates with 10% fetal bovine serum in the cell growth study. TUNEL assay was performed to detect the effect of the MYCT1 gene on the apoptosis of cells. The ratio of MYCT1 gene expression to β-actin gene expression was 0.47 ± 0.01 and 0.76 ± 0.01 for human gastric cancer cell lines and human embryonic kidney cell lines, respectively. MYCT1 gene expression was downregulated in the human gastric cancer cell lines than human embryonic kidney cell line (p < 0.001). MYCT1 gene decreased cell growth (p = 0.041) during 6 days of incubation study of cells. TUNEL assay showed only the fluorescence of PI in BGC823 cells without the MYCT1 gene. MYCT1 gene expression was downregulated in the human gastric cancer cell lines, and MYCT1 gene accelerates the apoptotic process.
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Affiliation(s)
- Xiangning Dong
- Department of Oncology, The First People's Hospital of Chuzhou, The Affiliated Chuzhou Hospital of Anhui Medical University, Chuzhou, China.
| | - Song Xue
- Department of Oncology, The First People's Hospital of Chuzhou, The Affiliated Chuzhou Hospital of Anhui Medical University, Chuzhou, China
| | - Chen Chen
- Department of Ultrasound, The First People's Hospital of Chuzhou, The Affiliated Chuzhou Hospital of Anhui Medical University, Chuzhou, China
| | - Zonghui Jiang
- Department of Oncology, The First People's Hospital of Chuzhou, The Affiliated Chuzhou Hospital of Anhui Medical University, Chuzhou, China
| | - Xiangdu Wu
- Department of Gastroenterology, The First People's Hospital of Chuzhou, The Affiliated Chuzhou Hospital of Anhui Medical University, Chuzhou, China
| | - Weifei Wang
- Department of Oncology, The First People's Hospital of Chuzhou, The Affiliated Chuzhou Hospital of Anhui Medical University, Chuzhou, China
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Xin S, Zhang Y, Zhang Z, Li Z, Sun X, Liu X, Jin L, Li W, Tang C, Mei W, Cao Q, Wang H, Wei Z, Zhou Z, Li R, Wen X, Yang G, Chen W, Zheng J, Ye L. ScRNA-seq revealed the tumor microenvironment heterogeneity related to the occurrence and metastasis in upper urinary tract urothelial carcinoma. Cancer Gene Ther 2024; 31:1201-1220. [PMID: 38877164 DOI: 10.1038/s41417-024-00779-3] [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: 12/13/2023] [Revised: 04/15/2024] [Accepted: 04/22/2024] [Indexed: 06/16/2024]
Abstract
Metastasis is the greatest clinical challenge for UTUCs, which may have distinct molecular and cellular characteristics from earlier cancers. Herein, we provide single-cell transcriptome profiles of UTUC para cancer normal tissue, primary tumor lesions, and lymphatic metastases to explore possible mechanisms associated with UTUC occurrence and metastasis. From 28,315 cells obtained from normal and tumor tissues of 3 high-grade UTUC patients, we revealed the origin of UTUC tumor cells and the homology between metastatic and primary tumor cells. Unlike the immunomicroenvironment suppression of other tumors, we found no immunosuppression in the tumor microenvironment of UTUC. Moreover, it is imperative to note that stromal cells are pivotal in the advancement of UTUC. This comprehensive single-cell exploration enhances our comprehension of the molecular and cellular dynamics of metastatic UTUCs and discloses promising diagnostic and therapeutic targets in cancer-microenvironment interactions.
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Affiliation(s)
- Shiyong Xin
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
- Department of Urology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471000, China
| | - Yanwei Zhang
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Zhenhua Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Ziyao Li
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Xianchao Sun
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Xiang Liu
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Liang Jin
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Weiyi Li
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Chaozhi Tang
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Wangli Mei
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Qiong Cao
- Department of Pathology, The Third Affiliated Hospital of Henan University of Science and Technology, Luoyang, 471003, China
| | - Haojie Wang
- Department of Central Laboratory, Zhengzhou University, Luoyang Central Hospital, Luoyang, 471003, China
| | - Zhihao Wei
- Department of Pathology, Yiluo Hospital of Luoyang, The Teaching Hospital of Henan University of Science and Technology, Luoyang, China
| | - Zhen Zhou
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Rongbing Li
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Xiaofei Wen
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Guosheng Yang
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Weihua Chen
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
| | - Junhua Zheng
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
| | - Lin Ye
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
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7
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Ban Y, Zou Y, Liu Y, Lee SB, Bednarczyk RB, Sheng J, Cao Y, Wong STC, Gao D. Targeting Ribosome Biogenesis as a Novel Therapeutic Approach to Overcome EMT-related Chemoresistance in Breast Cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.06.28.546927. [PMID: 37425795 PMCID: PMC10327026 DOI: 10.1101/2023.06.28.546927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
Epithelial-to-mesenchymal transition (EMT) contributes significantly to chemotherapy resistance and remains a critical challenge in treating advanced breast cancer. The complexity of EMT, involving redundant pro-EMT signaling pathways and its paradox reversal process, mesenchymal-to-epithelial transition (MET), has hindered the development of effective treatments. In this study, we utilized a Tri-PyMT EMT lineage-tracing model and single-cell RNA sequencing (scRNA-seq) to comprehensively analyze the EMT status of tumor cells. Our findings revealed elevated ribosome biogenesis (RiBi) during the transitioning phases of both EMT and MET processes. RiBi and its subsequent nascent protein synthesis mediated by ERK and mTOR signalings are essential for EMT/MET completion. Importantly, inhibiting excessive RiBi genetically or pharmacologically impaired the EMT/MET capability of tumor cells. Combining RiBi inhibition with chemotherapy drugs synergistically reduced metastatic outgrowth of epithelial and mesenchymal tumor cells under chemotherapies. Our study suggests that targeting the RiBi pathway presents a promising strategy for treating patients with advanced breast cancer. Significance This study uncovers the crucial involvement of ribosome biogenesis (RiBi) in the regulation of epithelial and mesenchymal state oscillations in breast cancer cells, which plays a major role in the development of chemoresistant metastasis. By proposing a novel therapeutic strategy targeting the RiBi pathway, the study offers significant potential to enhance treatment efficacy and outcomes for patients with advanced breast cancer. This approach could help overcome the limitations of current chemotherapy options and address the complex challenges posed by EMT-mediated chemoresistance.
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Silva AO, Bitencourt TC, Vargas JE, Fraga LR, Filippi-Chiela E. Modulation of tumor plasticity by senescent cells: Deciphering basic mechanisms and survival pathways to unravel therapeutic options. Genet Mol Biol 2024; 47Suppl 1:e20230311. [PMID: 38805699 PMCID: PMC11132560 DOI: 10.1590/1678-4685-gmb-2023-0311] [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: 11/02/2023] [Accepted: 03/21/2024] [Indexed: 05/30/2024] Open
Abstract
Senescence is a cellular state in which the cell loses its proliferative capacity, often irreversibly. Physiologically, it occurs due to a limited capacity of cell division associated with telomere shortening, the so-called replicative senescence. It can also be induced early due to DNA damage, oncogenic activation, oxidative stress, or damage to other cellular components (collectively named induced senescence). Tumor cells acquire the ability to bypass replicative senescence, thus ensuring the replicative immortality, a hallmark of cancer. Many anti-cancer therapies, however, can lead tumor cells to induced senescence. Initially, this response leads to a slowdown in tumor growth. However, the longstanding accumulation of senescent cells (SnCs) in tumors can promote neoplastic progression due to the enrichment of numerous molecules and extracellular vesicles that constitutes the senescence-associated secretory phenotype (SASP). Among other effects, SASP can potentiate or unlock the tumor plasticity and phenotypic transitions, another hallmark of cancer. This review discusses how SnCs can fuel mechanisms that underlie cancer plasticity, like cell differentiation, stemness, reprogramming, and epithelial-mesenchymal transition. We also discuss the main molecular mechanisms that make SnCs resistant to cell death, and potential strategies to target SnCs. At the end, we raise open questions and clinically relevant perspectives in the field.
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Affiliation(s)
- Andrew Oliveira Silva
- Faculdade Estácio, Porto Alegre, RS, Brazil
- Centro de Pesquisa Experimental, Hospital de Clínicas de Porto
Alegre, Porto Alegre, RS, Brazil
| | - Thais Cardoso Bitencourt
- Centro de Pesquisa Experimental, Hospital de Clínicas de Porto
Alegre, Porto Alegre, RS, Brazil
- Universidade Federal do Rio Grande do Sul, Programa de Pós-Graduação
em Biologia Celular e Molecular, Porto Alegre, RS, Brazil
| | - Jose Eduardo Vargas
- Universidade Federal do Paraná, Departamento de Biologia Celular,
Curitiba, PR, Brazil
| | - Lucas Rosa Fraga
- Centro de Pesquisa Experimental, Hospital de Clínicas de Porto
Alegre, Porto Alegre, RS, Brazil
- Universidade Federal do Rio Grande do Sul, Departamento de Ciências
Morfológicas, Porto Alegre, RS, Brazil
- Universidade Federal do Rio Grande do Sul, Programa de Pós-Graduação
em Medicina: Ciências Médicas, Porto Alegre, RS, Brazil
| | - Eduardo Filippi-Chiela
- Centro de Pesquisa Experimental, Hospital de Clínicas de Porto
Alegre, Porto Alegre, RS, Brazil
- Universidade Federal do Rio Grande do Sul, Departamento de Ciências
Morfológicas, Porto Alegre, RS, Brazil
- Universidade Federal do Rio Grande do Sul, Centro de Biotecnologia,
Porto Alegre, RS, Brazil
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Li Y, Zheng Y, Xu S, Hu H, Peng L, Zhu J, Wu M. The nanobody targeting PD-L1 and CXCR4 counteracts pancreatic stellate cell-mediated tumour progression by disrupting tumour microenvironment. Int Immunopharmacol 2024; 132:111944. [PMID: 38581990 DOI: 10.1016/j.intimp.2024.111944] [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: 11/28/2023] [Revised: 03/11/2024] [Accepted: 03/25/2024] [Indexed: 04/08/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy worldwide owing to its complex tumour microenvironment and dense physical barriers. Stromal-derived factor-1 (SDF-1), which is abundantly secreted by tumour stromal cells, plays a pivotal role in promoting PDAC growth and metastasis. In this study, we investigated the impact and molecular mechanisms of the anti-PD-L1&CXCR4 bispecific nanobody on the TME and their consequent interference with PDAC progression. We found that blocking the SDF-1/CXCR4 signalling pathway delayed the epithelial-mesenchymal transition in pancreatic cancer cells. Anti-PD-L1&CXCR4 bispecific nanobody effectively suppress the secretion of SDF-1 by pancreatic stellate cells and downregulate the expression of smooth muscle actin alpha(α-SMA), thereby preventing the activation of cancer-associated fibroblasts by downregulating the PI3K/AKT signaling pathway. This improves the pancreatic tumour microenvironment, favouring the infiltration of T cells into the tumour tissue. In conclusion, our results suggest that the anti-PD-L1&CXCR4 bispecific nanobody exerts an antitumor immune response by changing the pancreatic tumour microenvironment. Hence, the anti-PD-L1&CXCR4 bispecific nanobody is a potential candidate for pancreatic cancer treatment.
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Affiliation(s)
- Yaxian Li
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, People's Republic of China.
| | - Yuejiang Zheng
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, People's Republic of China
| | - Shuyi Xu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, People's Republic of China.
| | - Hai Hu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, People's Republic of China
| | - Liyun Peng
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, People's Republic of China
| | - Jianwei Zhu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, People's Republic of China
| | - Mingyuan Wu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, People's Republic of China.
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10
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Ren Z, Dharmaratne M, Liang H, Benard O, Morales-Gallego M, Suyama K, Kumar V, Fard AT, Kulkarni AS, Prystowsky M, Mar JC, Norton L, Hazan RB. Redox signalling regulates breast cancer metastasis via phenotypic and metabolic reprogramming due to p63 activation by HIF1α. Br J Cancer 2024; 130:908-924. [PMID: 38238426 PMCID: PMC10951347 DOI: 10.1038/s41416-023-02522-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 11/08/2023] [Accepted: 11/24/2023] [Indexed: 03/21/2024] Open
Abstract
BACKGROUND Redox signaling caused by knockdown (KD) of Glutathione Peroxidase 2 (GPx2) in the PyMT mammary tumour model promotes metastasis via phenotypic and metabolic reprogramming. However, the tumour cell subpopulations and transcriptional regulators governing these processes remained unknown. METHODS We used single-cell transcriptomics to decipher the tumour cell subpopulations stimulated by GPx2 KD in the PyMT mammary tumour and paired pulmonary metastases. We analyzed the EMT spectrum across the various tumour cell clusters using pseudotime trajectory analysis and elucidated the transcriptional and metabolic regulation of the hybrid EMT state. RESULTS Integration of single-cell transcriptomics between the PyMT/GPx2 KD primary tumour and paired lung metastases unraveled a basal/mesenchymal-like cluster and several luminal-like clusters spanning an EMT spectrum. Interestingly, the luminal clusters at the primary tumour gained mesenchymal gene expression, resulting in epithelial/mesenchymal subpopulations fueled by oxidative phosphorylation (OXPHOS) and glycolysis. By contrast, at distant metastasis, the basal/mesenchymal-like cluster gained luminal and mesenchymal gene expression, resulting in a hybrid subpopulation using OXPHOS, supporting adaptive plasticity. Furthermore, p63 was dramatically upregulated in all hybrid clusters, implying a role in regulating partial EMT and MET at primary and distant sites, respectively. Importantly, these effects were reversed by HIF1α loss or GPx2 gain of function, resulting in metastasis suppression. CONCLUSIONS Collectively, these results underscored a dramatic effect of redox signaling on p63 activation by HIF1α, underlying phenotypic and metabolic plasticity leading to mammary tumour metastasis.
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Affiliation(s)
- Zuen Ren
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Malindrie Dharmaratne
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia
| | - Huizhi Liang
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | | | | | - Kimita Suyama
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Viney Kumar
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Atefeh Taherian Fard
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia
| | - Ameya S Kulkarni
- Department of Endocrinology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Michael Prystowsky
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Jessica C Mar
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia
| | - Larry Norton
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, 10021, USA
| | - Rachel B Hazan
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
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Cicero J, Trouvilliez S, Palma M, Ternier G, Decoster L, Happernegg E, Barois N, Van Outryve A, Dehouck L, Bourette RP, Adriaenssens E, Lagadec C, Tarhan CM, Collard D, Souguir Z, Vandenhaute E, Maubon G, Sipieter F, Borghi N, Shimizu F, Kanda T, Giacobini P, Gosselet F, Maubon N, Le Bourhis X, Van Seuningen I, Mysiorek C, Toillon RA. ProNGF promotes brain metastasis through TrkA/EphA2 induced Src activation in triple negative breast cancer cells. Exp Hematol Oncol 2023; 12:104. [PMID: 38072918 PMCID: PMC10710730 DOI: 10.1186/s40164-023-00463-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 11/29/2023] [Indexed: 10/16/2024] Open
Abstract
BACKGROUND Triple-Negative Breast Cancer is particularly aggressive, and its metastasis to the brain has a significant psychological impact on patients' quality of life, in addition to reducing survival. The development of brain metastases is particularly harmful in triple-negative breast cancer (TNBC). To date, the mechanisms that induce brain metastasis in TNBC are poorly understood. METHODS Using a human blood-brain barrier (BBB) in vitro model, an in vitro 3D organotypic extracellular matrix, an ex vivo mouse brain slices co-culture and in an in vivo xenograft experiment, key step of brain metastasis were recapitulated to study TNBC behaviors. RESULTS In this study, we demonstrated for the first time the involvement of the precursor of Nerve Growth Factor (proNGF) in the development of brain metastasis. More importantly, our results showed that proNGF acts through TrkA independent of its phosphorylation to induce brain metastasis in TNBC. In addition, we found that proNGF induces BBB transmigration through the TrkA/EphA2 signaling complex. More importantly, our results showed that combinatorial inhibition of TrkA and EphA2 decreased TBNC brain metastasis in a preclinical model. CONCLUSIONS These disruptive findings provide new insights into the mechanisms underlying brain metastasis with proNGF as a driver of brain metastasis of TNBC and identify TrkA/EphA2 complex as a potential therapeutic target.
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Affiliation(s)
- Julien Cicero
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- Laboratoire de La Barrière Hémato-Encéphalique (LBHE), University of Artois, UR 2465, F-62300, Lens, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
| | - Sarah Trouvilliez
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
| | - Martine Palma
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
| | - Gaetan Ternier
- UMR-S1172, University of Lille, Inserm, CHU Lille, Équipe Développement et Plasticité du cerveau neuroendocrine, Lille Neuroscience et Cognition, 1 Place de Verdun, 59000, Lille Cedex, France
| | - Laurine Decoster
- UMR-S1172, University of Lille, Inserm, CHU Lille, Équipe Développement et Plasticité du cerveau neuroendocrine, Lille Neuroscience et Cognition, 1 Place de Verdun, 59000, Lille Cedex, France
| | - Eloise Happernegg
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- Laboratoire de La Barrière Hémato-Encéphalique (LBHE), University of Artois, UR 2465, F-62300, Lens, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
| | - Nicolas Barois
- University of Lille, CNRS, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, 59000, Lille, Inserm, France
| | - Alexandre Van Outryve
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
- UMR 8520 -IEMN - Institut d'Electronique de Microélectronique et de Nanotechnologie, University of Lille, CNRS, Centrale Lille, Junia, University Polytechnique Hauts-de-France, 59000, Lille, France
| | - Lucie Dehouck
- Laboratoire de La Barrière Hémato-Encéphalique (LBHE), University of Artois, UR 2465, F-62300, Lens, France
| | - Roland P Bourette
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
| | - Eric Adriaenssens
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
| | - Chann Lagadec
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
| | - Cagatay Mehmet Tarhan
- UMR 8520 -IEMN - Institut d'Electronique de Microélectronique et de Nanotechnologie, University of Lille, CNRS, Centrale Lille, Junia, University Polytechnique Hauts-de-France, 59000, Lille, France
- LIMMS/CNRS-IIS IRL2820, The University of Tokyo, Tokyo, Japan
| | - Dominique Collard
- LIMMS/CNRS-IIS IRL2820, The University of Tokyo, Tokyo, Japan
- CNRS, IIS, University of Lille SMMiL-E Project, 59000, Lille, COL, France
| | | | | | | | - François Sipieter
- Université Paris Cité, Centre National de La Recherche Scientifique (CNRS), Institut Jacques Monod, 15 rue Hélène Brion, 75013, Paris, France
| | - Nicolas Borghi
- Université Paris Cité, Centre National de La Recherche Scientifique (CNRS), Institut Jacques Monod, 15 rue Hélène Brion, 75013, Paris, France
| | - Fumitaka Shimizu
- Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Takashi Kanda
- Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Paolo Giacobini
- UMR-S1172, University of Lille, Inserm, CHU Lille, Équipe Développement et Plasticité du cerveau neuroendocrine, Lille Neuroscience et Cognition, 1 Place de Verdun, 59000, Lille Cedex, France
| | - Fabien Gosselet
- Laboratoire de La Barrière Hémato-Encéphalique (LBHE), University of Artois, UR 2465, F-62300, Lens, France
| | | | - Xuefen Le Bourhis
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
| | - Isabelle Van Seuningen
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
| | - Caroline Mysiorek
- Laboratoire de La Barrière Hémato-Encéphalique (LBHE), University of Artois, UR 2465, F-62300, Lens, France
| | - Robert-Alain Toillon
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France.
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France.
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12
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Wang X, Eichhorn PJA, Thiery JP. TGF-β, EMT, and resistance to anti-cancer treatment. Semin Cancer Biol 2023; 97:1-11. [PMID: 37944215 DOI: 10.1016/j.semcancer.2023.10.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 05/08/2023] [Accepted: 10/16/2023] [Indexed: 11/12/2023]
Abstract
Transforming growth factor-β (TGF-β) signaling regulates cell-specific programs involved in embryonic development, wound-healing, and immune homeostasis. Yet, during tumor progression, these TGF-β-mediated programs are altered, leading to epithelial cell plasticity and a reprogramming of epithelial cells into mesenchymal lineages through epithelial-to-mesenchymal transition (EMT), a critical developmental program in morphogenesis and organogenesis. These changes, in turn, lead to enhanced carcinoma cell invasion, metastasis, immune cell differentiation, immune evasion, and chemotherapy resistance. Here, we discuss EMT as one of the critical programs associated with carcinoma cell plasticity and the influence exerted by TGF-β on carcinoma status and function. We further explore the composition of carcinoma and other cell populations within the tumor microenvironment, and consider the relevant outcomes related to the programs associated with cancer treatment resistance.
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Affiliation(s)
- Xuecong Wang
- Guangzhou National Laboratory, Guangzhou, China; Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
| | - Pieter Johan Adam Eichhorn
- Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, GPO Box U1987, Perth, WA 6845, Australia; Curtin Medical School, Curtin University, GPO Box U1987, Perth, WA 6845, Australia; Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore, Singapore
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13
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Xu Y, Cai H, Xiong Y, Tang L, Li L, Zhang L, Shen Y, Yang Y, Lin L, Huang J. YAP/TAZ axis was involved in the effects of metformin on breast cancer. J Chemother 2023; 35:627-637. [PMID: 36656142 DOI: 10.1080/1120009x.2022.2162221] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 11/24/2022] [Accepted: 12/19/2022] [Indexed: 01/20/2023]
Abstract
Breast cancer is malignant tumours in women. A large amount of data analysis shows that Metformin has been shown to play a significance role in reducing the risk of breast cancer, but the mechanism remains unclear. The hippo signalling pathway can be involved in the formation, metastasis and recurrence of breast cancer. When YAP/TAZ is activated, cells can overcome contact inhibition and enter a state of uncontrolled proliferation. Therefore, YAP/TAZ is considered a potential therapeutic target for breast cancer. Eighty breast cancer patients, forty cases of triple-negative and forty cases of HER-2+, were included in this study. In vitro and in vivo experiments were used to confirm the YAP/TAZ axis was involved in the effects of metformin on breast cancer. EMT plays an important role in breast cancer, including chemoresistance and tumour metastasis. Our results confirmed that YAP could modulate the activity of EMT, which in turn altered tumour resistance. Therefore, MET can inhibit EMT by reducing the expression of YAP, and finally achieve the therapeutic effect of breast cancer. Our findings support metformin as a novel YAP inhibitor and potentially as a novel breast cancer drug.
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Affiliation(s)
- Yu Xu
- Department of Pathophysiology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Hongke Cai
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuanfeng Xiong
- Department of Pathophysiology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Li Tang
- Department of Pathophysiology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Longjiang Li
- Department of Pathophysiology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Li Zhang
- Department of Pathophysiology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Yi Shen
- Department of Pathophysiology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Yongqiang Yang
- Department of Pathophysiology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Ling Lin
- Department of Pathophysiology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Jiayi Huang
- Department of Pathophysiology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
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14
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Shyam S, Ramu S, Sehgal M, Jolly MK. A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity. J R Soc Interface 2023; 20:20230389. [PMID: 37963558 PMCID: PMC10645512 DOI: 10.1098/rsif.2023.0389] [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: 07/09/2023] [Accepted: 10/20/2023] [Indexed: 11/16/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) is an important axis of phenotypic plasticity-a hallmark of cancer metastasis. Raf kinase-B inhibitor protein (RKIP) and BTB and CNC homology 1 (BACH1) are reported to influence EMT. In breast cancer, they act antagonistically, but the exact nature of their roles in mediating EMT and associated other axes of plasticity remains unclear. Here, analysing transcriptomic data, we reveal their antagonistic trends in a pan-cancer manner in terms of association with EMT, metabolic reprogramming and immune evasion via PD-L1. Next, we developed and simulated a mechanism-based gene regulatory network that captures how RKIP and BACH1 engage in feedback loops with drivers of EMT and stemness. We found that RKIP and BACH1 belong to two antagonistic 'teams' of players-while BACH1 belonged to the one driving pro-EMT, stem-like and therapy-resistant cell states, RKIP belonged to the one enabling pro-epithelial, less stem-like and therapy-sensitive phenotypes. Finally, we observed that low RKIP levels and upregulated BACH1 levels associated with worse clinical outcomes in many cancer types. Together, our systems-level analysis indicates that the emergent dynamics of underlying regulatory network enable the antagonistic patterns of RKIP and BACH1 with various axes of cancer cell plasticity, and with patient survival data.
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Affiliation(s)
- Sai Shyam
- Department of Bioengineering, Indian Institute of Science, Bangalore 560012, India
| | - Soundharya Ramu
- Department of Bioengineering, Indian Institute of Science, Bangalore 560012, India
| | - Manas Sehgal
- Department of Bioengineering, Indian Institute of Science, Bangalore 560012, India
| | - Mohit Kumar Jolly
- Department of Bioengineering, Indian Institute of Science, Bangalore 560012, India
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15
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Liu Y, Tang W, Yao F. USP53 Exerts Tumor-Promoting Effects in Triple-Negative Breast Cancer by Deubiquitinating CRKL. Cancers (Basel) 2023; 15:5033. [PMID: 37894400 PMCID: PMC10605207 DOI: 10.3390/cancers15205033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 10/03/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Breast cancer (BC) ranks in the top five malignant tumors in terms of morbidity and mortality rates. Among BC subtypes, TNBC has a high recurrence rate and metastasis rate and the worst prognosis. However, the exact mechanism by which TNBC develops is unclear. Here, we show that the deubiquitinase USP53 contributes to tumor growth and metastasis in TNBC. USP53 is overexpressed in TNBC, and this phenotype is linked to a poor prognosis. Functionally, USP53 promotes TNBC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). More importantly, USP53 decreases the chemosensitivity of BC cells by enhancing v-crk sarcoma virus CT10 oncogene homologue (avian)-like (CRKL) expression. Mechanistically, USP53 directly binds CRKL to stabilize and deubiquitinate it, thereby preventing CRKL degradation. Overall, we discovered that USP53 deubiquitinates CRKL, encourages tumor development and metastasis, and reduces chemosensitivity in TNBC. These findings imply that USP53 might represent a new therapeutic target for the treatment of TNBC.
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Affiliation(s)
- Yi Liu
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China;
| | - Wei Tang
- Department of Pediartrics, Renmin Hospital of Wuhan University, Wuhan 430060, China;
| | - Feng Yao
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China;
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16
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Dou R, Han L, Yang C, Fang Y, Zheng J, Liang C, Song J, Wei C, Huang G, Zhong P, Liu K, Peng Q, Peng C, Xiong B, Wang S. Upregulation of LINC00501 by H3K27 acetylation facilitates gastric cancer metastasis through activating epithelial-mesenchymal transition and angiogenesis. Clin Transl Med 2023; 13:e1432. [PMID: 37867401 PMCID: PMC10591115 DOI: 10.1002/ctm2.1432] [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: 03/13/2023] [Revised: 09/11/2023] [Accepted: 09/30/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND The molecular mechanism of the significant role of long noncoding RNAs (lncRNAs) in the progression and metastasis of gastric cancer (GC) remains largely elusive. Our objective is to detect overexpressed lncRNA in GC and investigate its role in promoting epithelial-mesenchymal transition and tumour microenvironment remodel. METHODS LncRNA differential expression profile in GC was analysed using RNA microarrays. The level of LINC00501 was evaluated in both GC patient tissues and GC cell lines by quantitative reverse transcription PCR and large-scale (n = 304) tissue microarray. To explore the biological role and regulatory driver of LINC00501 in GC, various experimental techniques including Chromatin isolation by RNA purification (ChIRP), RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP) assay, dual luciferase assays were performed. RESULTS Clinically, it was observed that LINC00501 level was abnormal overexpression in GC tissue and was associated with GC progression and distant metastasis. Gain and loss molecular biological experiments suggested that LINC00501, promoted EMT process and angiogenesis of GC. Mechanically, the enrichment of H3K27 acetylation in LINC00501 promoter region contributed to the increase of LINC00501 in GC. LINC00501 transactivated transcription of SLUG, by recruiting hnRNPR to its promoter. The growth of GC was inhibited both in vitro and in vivo by suppressing the level of LINC00501 using pharmacological intervention from the histone acetyltransferase (HAT) inhibitor -C646. CONCLUSIONS This study suggests that LINC00501 promotes GC progression via hnRNPR/SLUG pathway, which indicates a promising biomarker and target for GC.
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Affiliation(s)
- Rongzhang Dou
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Lei Han
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Chaogang Yang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Yan Fang
- Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong, China
| | - Jinsen Zheng
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Chenxi Liang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Jialin Song
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Chen Wei
- Department of Internal Medicine, Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Guoquan Huang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Panyi Zhong
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Keshu Liu
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Qian Peng
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Chunwei Peng
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Bin Xiong
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Shuyi Wang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
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17
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Subbalakshmi AR, Sahoo S, Manjunatha P, Goyal S, Kasiviswanathan VA, Mahesh Y, Ramu S, McMullen I, Somarelli JA, Jolly MK. The ELF3 transcription factor is associated with an epithelial phenotype and represses epithelial-mesenchymal transition. J Biol Eng 2023; 17:17. [PMID: 36864480 PMCID: PMC9983220 DOI: 10.1186/s13036-023-00333-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 02/09/2023] [Indexed: 03/04/2023] Open
Abstract
BACKGROUND Epithelial-mesenchymal plasticity (EMP) involves bidirectional transitions between epithelial, mesenchymal and multiple intermediary hybrid epithelial/mesenchymal phenotypes. While the process of epithelial-mesenchymal transition (EMT) and its associated transcription factors are well-characterised, the transcription factors that promote mesenchymal-epithelial transition (MET) and stabilise hybrid E/M phenotypes are less well understood. RESULTS Here, we analyse multiple publicly-available transcriptomic datasets at bulk and single-cell level and pinpoint ELF3 as a factor that is strongly associated with an epithelial phenotype and is inhibited during EMT. Using mechanism-based mathematical modelling, we also show that ELF3 inhibits the progression of EMT. This behaviour was also observed in the presence of an EMT inducing factor WT1. Our model predicts that the MET induction capacity of ELF3 is stronger than that of KLF4, but weaker than that of GRHL2. Finally, we show that ELF3 levels correlates with worse patient survival in a subset of solid tumour types. CONCLUSION ELF3 is shown to be inhibited during EMT progression and is also found to inhibit the progression of complete EMT suggesting that ELF3 may be able to counteract EMT induction, including in the presence of EMT-inducing factors, such as WT1. The analysis of patient survival data indicates that the prognostic capacity of ELF3 is specific to cell-of-origin or lineage.
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Affiliation(s)
- Ayalur Raghu Subbalakshmi
- grid.34980.360000 0001 0482 5067Centre for BioSystems Science and Engineering, Indian Institute of Science, 560012 Bangalore, India
| | - Sarthak Sahoo
- grid.34980.360000 0001 0482 5067Centre for BioSystems Science and Engineering, Indian Institute of Science, 560012 Bangalore, India
| | - Prakruthi Manjunatha
- grid.444321.40000 0004 0501 2828Department of Medical Electronics, M S Ramaiah Institute of Technology, 560054 Bangalore, India
| | - Shaurya Goyal
- grid.429017.90000 0001 0153 2859Department of Humanities and Social Sciences, Indian Institute of Technology, 721302 Kharagpur, India
| | - Vignesh A Kasiviswanathan
- grid.512757.30000 0004 1761 9897Department of Biotechnology, JSS Science and Technology University, 570006 Mysore, India
| | - Yeshwanth Mahesh
- grid.34980.360000 0001 0482 5067Centre for BioSystems Science and Engineering, Indian Institute of Science, 560012 Bangalore, India
| | - Soundharya Ramu
- grid.419655.a0000 0001 0008 3668Department of Biotechnology, National Institute of Technology Warangal, 506004 Warangal, India
| | - Isabelle McMullen
- grid.26009.3d0000 0004 1936 7961Department of Medicine, Duke University, NC 27708 Durham, USA
| | - Jason A. Somarelli
- grid.26009.3d0000 0004 1936 7961Department of Medicine, Duke University, NC 27708 Durham, USA ,grid.26009.3d0000 0004 1936 7961Duke Cancer Institute, Duke University, NC 27708 Durham, USA
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, 560012, Bangalore, India.
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18
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Regulation of the Epithelial to Mesenchymal Transition in Osteosarcoma. Biomolecules 2023; 13:biom13020398. [PMID: 36830767 PMCID: PMC9953423 DOI: 10.3390/biom13020398] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/09/2023] [Accepted: 02/14/2023] [Indexed: 02/22/2023] Open
Abstract
The epithelial to mesenchymal transition (EMT) is a cellular process that has been linked to the promotion of aggressive cellular features in many cancer types. It is characterized by the loss of the epithelial cell phenotype and a shift to a more mesenchymal phenotype and is accompanied by an associated change in cell markers. EMT is highly complex and regulated via multiple signaling pathways. While the importance of EMT is classically described for carcinomas-cancers of epithelial origin-it has also been clearly demonstrated in non-epithelial cancers, including osteosarcoma (OS), a primary bone cancer predominantly affecting children and young adults. Recent studies examining EMT in OS have highlighted regulatory roles for multiple proteins, non-coding nucleic acids, and components of the tumor micro-environment. This review serves to summarize these experimental findings, identify key families of regulatory molecules, and identify potential therapeutic targets specific to the EMT process in OS.
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19
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Zhang L, Chen W, Liu S, Chen C. Targeting Breast Cancer Stem Cells. Int J Biol Sci 2023; 19:552-570. [PMID: 36632469 PMCID: PMC9830502 DOI: 10.7150/ijbs.76187] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 12/09/2022] [Indexed: 01/04/2023] Open
Abstract
The potential roles of breast cancer stem cells (BCSCs) in tumor initiation and recurrence have been recognized for many decades. Due to their strong capacity for self-renewal and differentiation, BCSCs are the major reasons for poor clinical outcomes and low therapeutic response. Several hypotheses on the origin of cancer stem cells have been proposed, including critical gene mutations in stem cells, dedifferentiation of somatic cells, and cell plasticity remodeling by epithelial-mesenchymal transition (EMT) and the tumor microenvironment. Moreover, the tumor microenvironment, including cellular components and cytokines, modulates the self-renewal and therapeutic resistance of BCSCs. Small molecules, antibodies, and chimeric antigen receptor (CAR)-T cells targeting BCSCs have been developed, and their applications in combination with conventional therapies are undergoing clinical trials. In this review, we focus on the features of BCSCs, emphasize the major factors and tumor environment that regulate the stemness of BCSCs, and discuss potential BCSC-targeting therapies.
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Affiliation(s)
- Lu Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai paracrine Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai 200032, China
| | - Wenmin Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming 650201, China.,Kunming College of Life Sciences, the University of the Chinese Academy of Sciences, Kunming 650201, China
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; State Key Laboratory of Genetic Engineering; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; The Shanghai paracrine Key Laboratory of Medical Epigenetics; Shanghai Key Laboratory of Radiation Oncology; The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology; Shanghai Medical College; Fudan University, Shanghai 200032, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing 211166, China.,✉ Corresponding authors: Ceshi Chen, E-mail: or Suling Liu, E-mail:
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming 650201, China.,Academy of Biomedical Engineering, Kunming Medical University, Kunming 650500, China.,The Third Affiliated Hospital, Kunming Medical University, Kunming 650118, China.,✉ Corresponding authors: Ceshi Chen, E-mail: or Suling Liu, E-mail:
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20
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Niu ZS, Wang WH, Niu XJ. Recent progress in molecular mechanisms of postoperative recurrence and metastasis of hepatocellular carcinoma. World J Gastroenterol 2022; 28:6433-6477. [PMID: 36569275 PMCID: PMC9782839 DOI: 10.3748/wjg.v28.i46.6433] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 10/31/2022] [Accepted: 11/21/2022] [Indexed: 12/08/2022] Open
Abstract
Hepatectomy is currently considered the most effective option for treating patients with early and intermediate hepatocellular carcinoma (HCC). Unfortunately, the postoperative prognosis of patients with HCC remains unsatisfactory, predominantly because of high postoperative metastasis and recurrence rates. Therefore, research on the molecular mechanisms of postoperative HCC metastasis and recurrence will help develop effective intervention measures to prevent or delay HCC metastasis and recurrence and to improve the long-term survival of HCC patients. Herein, we review the latest research progress on the molecular mechanisms underlying postoperative HCC metastasis and recurrence to lay a foundation for improving the understanding of HCC metastasis and recurrence and for developing more precise prevention and intervention strategies.
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Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Xiao-Jun Niu
- Department of Internal Medicine, Qingdao Shibei District People's Hospital, Qingdao 266033, Shandong Province, China
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21
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Castaneda M, den Hollander P, Kuburich NA, Rosen JM, Mani SA. Mechanisms of cancer metastasis. Semin Cancer Biol 2022; 87:17-31. [PMID: 36354098 DOI: 10.1016/j.semcancer.2022.10.006] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 10/10/2022] [Accepted: 10/25/2022] [Indexed: 11/09/2022]
Abstract
Metastatic cancer is almost always terminal, and more than 90% of cancer deaths result from metastatic disease. Combating cancer metastasis and post-therapeutic recurrence successfully requires understanding each step of metastatic progression. This review describes the current state of knowledge of the etiology and mechanism of cancer progression from primary tumor growth to the formation of new tumors in other parts of the body. Open questions, avenues for future research, and therapeutic approaches with the potential to prevent or inhibit metastasis through personalization to each patient's mutation and/or immune profile are also highlighted.
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Affiliation(s)
- Maria Castaneda
- Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Petra den Hollander
- Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology and Lab Medicine, Brown University, Providence, RI 02912, USA; Legoretta Cancer Center, Brown University, Providence, RI 021912, USA
| | - Nick A Kuburich
- Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology and Lab Medicine, Brown University, Providence, RI 02912, USA; Legoretta Cancer Center, Brown University, Providence, RI 021912, USA
| | - Jeffrey M Rosen
- Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Sendurai A Mani
- Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology and Lab Medicine, Brown University, Providence, RI 02912, USA; Legoretta Cancer Center, Brown University, Providence, RI 021912, USA.
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22
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Kuburich NA, den Hollander P, Pietz JT, Mani SA. Vimentin and cytokeratin: Good alone, bad together. Semin Cancer Biol 2022; 86:816-826. [PMID: 34953942 PMCID: PMC9213573 DOI: 10.1016/j.semcancer.2021.12.006] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/26/2021] [Accepted: 12/14/2021] [Indexed: 01/27/2023]
Abstract
The cytoskeleton plays an integral role in maintaining the integrity of epithelial cells. Epithelial cells primarily employ cytokeratin in their cytoskeleton, whereas mesenchymal cells use vimentin. During the epithelial-mesenchymal transition (EMT), cytokeratin-positive epithelial cells begin to express vimentin. EMT induces stem cell properties and drives metastasis, chemoresistance, and tumor relapse. Most studies of the functions of cytokeratin and vimentin have relied on the use of either epithelial or mesenchymal cell types. However, it is important to understand how these two cytoskeleton intermediate filaments function when co-expressed in cells undergoing EMT. Here, we discuss the individual and shared functions of cytokeratin and vimentin that coalesce during EMT and how alterations in intermediate filament expression influence carcinoma progression.
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Affiliation(s)
- Nick A Kuburich
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Petra den Hollander
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Jordan T Pietz
- Department of Creative Services, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Sendurai A Mani
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
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23
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Cui Y, Wang X, Zhang L, Liu W, Ning J, Gu R, Cui Y, Cai L, Xing Y. A novel epithelial-mesenchymal transition (EMT)-related gene signature of predictive value for the survival outcomes in lung adenocarcinoma. Front Oncol 2022; 12:974614. [PMID: 36185284 PMCID: PMC9521574 DOI: 10.3389/fonc.2022.974614] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/30/2022] [Indexed: 11/24/2022] Open
Abstract
Lung adenocarcinoma (LUAD) is a remarkably heterogeneous and aggressive disease with dismal prognosis of patients. The identification of promising prognostic biomarkers might enable effective diagnosis and treatment of LUAD. Aberrant activation of epithelial-mesenchymal transition (EMT) is required for LUAD initiation, progression and metastasis. With the purpose of identifying a robust EMT-related gene signature (E-signature) to monitor the survival outcomes of LUAD patients. In The Cancer Genome Atlas (TCGA) database, least absolute shrinkage and selection operator (LASSO) analysis and cox regression analysis were conducted to acquire prognostic and EMT-related genes. A 4 EMT-related and prognostic gene signature, comprising dickkopf-like protein 1 (DKK1), lysyl oxidase-like 2 (LOXL2), matrix Gla protein (MGP) and slit guidance ligand 3 (SLIT3), was identified. By the usage of datum derived from TCGA database and Western blotting analysis, compared with adjacent tissue samples, DKK1 and LOXL2 protein expression in LUAD tissue samples were significantly higher, whereas the trend of MGP and SLIT3 expression were opposite. Concurrent with upregulation of epithelial markers and downregulation of mesenchymal markers, knockdown of DKK1 and LOXL2 impeded the migration and invasion of LUAD cells. Simultaneously, MGP and SLIT3 silencing promoted metastasis and induce EMT of LUAD cells. In the TCGA-LUAD set, receiver operating characteristic (ROC) analysis indicated that our risk model based on the identified E-signature was superior to those reported in literatures. Additionally, the E-signature carried robust prognostic significance. The validity of prediction in the E-signature was validated by the three independent datasets obtained from Gene Expression Omnibus (GEO) database. The probabilistic nomogram including the E-signature, pathological T stage and N stage was constructed and the nomogram demonstrated satisfactory discrimination and calibration. In LUAD patients, the E-signature risk score was associated with T stage, N stage, M stage and TNM stage. GSEA (gene set enrichment analysis) analysis indicated that the E-signature might be linked to the pathways including GLYCOLYSIS, MYC TARGETS, DNA REPAIR and so on. In conclusion, our study explored an innovative EMT based prognostic signature that might serve as a potential target for personalized and precision medicine.
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Affiliation(s)
- Yimeng Cui
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xin Wang
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Lei Zhang
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Wei Liu
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jinfeng Ning
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ruixue Gu
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yaowen Cui
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Li Cai
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- *Correspondence: Ying Xing, ; Li Cai,
| | - Ying Xing
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- *Correspondence: Ying Xing, ; Li Cai,
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24
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McGinn O, Riley D, Finlay-Schultz J, Paul KV, Kabos P, Sartorius CA. Cytokeratins 5 and 17 Maintain an Aggressive Epithelial State in Basal-Like Breast Cancer. Mol Cancer Res 2022; 20:1443-1455. [PMID: 35639459 PMCID: PMC9444965 DOI: 10.1158/1541-7786.mcr-21-0866] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 04/18/2022] [Accepted: 05/24/2022] [Indexed: 11/16/2022]
Abstract
Basal-like breast cancers (BLBC) are the most common triple-negative subtype (hormone receptor and HER2 negative) with poor short-term disease outcome and are commonly identified by expression of basal cytokeratins (CK) 5 and 17. The goal of this study was to investigate whether CK5 and CK17 play a role in adverse behavior of BLBC cells. BLBC cell lines contain heterogeneous populations of cells expressing CK5, CK17, and the mesenchymal filament protein vimentin. Stable shRNA knockdown of either CK5 or CK17 compared with non-targeting control in BLBC cells was sufficient to promote an epithelial-mesenchymal transition (EMT) gene signature with loss of E-cadherin and an increase in vimentin expression. Relative to control cells, CK5 and CK17 knockdown cells acquired a more spindle-like morphology with increased cell scattering and were more invasive in vitro. However, CK5 or CK17 knockdown compared with control cells generated decreased lymph node and lung metastases in vivo. Loss of CK5 or CK17 moderately reduced the IC50 dose of doxorubicin in vitro and led to increased doxorubicin efficacy in vivo. Single-cell RNA-sequencing of BLBC patient-derived xenografts identified heterogeneous populations of CK5/CK17, vimentin, and dual basal CK/vimentin-positive cells that fell on an EMT spectrum of epithelial, mesenchymal, and intermediate, respectively, whereas knockdown of CK5 transitioned cells toward a more mesenchymal score. IMPLICATIONS This study supports that basal CKs 5 and 17 contribute to the adverse behavior of BLBC cells and could be an untapped source of therapeutic vulnerability for this aggressive disease.
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Affiliation(s)
- Olivia McGinn
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Duncan Riley
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Jessica Finlay-Schultz
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kiran V. Paul
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Peter Kabos
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Carol A. Sartorius
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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25
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Coelho DR, Palma FR, Paviani V, He C, Danes JM, Huang Y, Calado JCP, Hart PC, Furdui CM, Poole LB, Schipma MJ, Bonini MG. Nuclear-localized, iron-bound superoxide dismutase-2 antagonizes epithelial lineage programs to promote stemness of breast cancer cells via a histone demethylase activity. Proc Natl Acad Sci U S A 2022; 119:e2110348119. [PMID: 35858297 PMCID: PMC9303987 DOI: 10.1073/pnas.2110348119] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 03/27/2022] [Indexed: 01/16/2023] Open
Abstract
The dichotomous behavior of superoxide dismutase-2 (SOD2) in cancer biology has long been acknowledged and more recently linked to different posttranslational forms of the enzyme. However, a distinctive activity underlying its tumor-promoting function is yet to be described. Here, we report that acetylation, one of such posttranslational modifications (PTMs), increases SOD2 affinity for iron, effectively changing the biochemical function of this enzyme from that of an antioxidant to a demethylase. Acetylated, iron-bound SOD2 localizes to the nucleus, promoting stem cell gene expression via removal of suppressive epigenetic marks such as H3K9me3 and H3K927me3. Particularly, H3K9me3 was specifically removed from regulatory regions upstream of Nanog and Oct-4, two pluripotency factors involved in cancer stem cell reprogramming. Phenotypically, cells expressing nucleus-targeted SOD2 (NLS-SOD2) have increased clonogenicity and metastatic potential. FeSOD2 operating as H3 demethylase requires H2O2 as substrate, which unlike cofactors of canonical demethylases (i.e., oxygen and 2-oxoglutarate), is more abundant in tumor cells than in normal tissue. Therefore, our results indicate that FeSOD2 is a demethylase with unique activities and functions in the promotion of cancer evolution toward metastatic phenotypes.
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Affiliation(s)
- Diego R. Coelho
- Department of Medicine, Division of Hematology Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
- Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
| | - Flavio R. Palma
- Department of Medicine, Division of Hematology Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
- Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
| | - Veronica Paviani
- Department of Medicine, Division of Hematology Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
- Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
| | - Chenxia He
- Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Medical College of Wisconsin, Milwaukee, WI 53226
| | - Jeanne M. Danes
- Department of Medicine, Division of Hematology Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
- Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
| | - Yunping Huang
- Department of Medicine, Division of Hematology Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
- Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
| | - Juliana C. P. Calado
- Department of Medicine, Division of Hematology Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
- Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
| | - Peter C. Hart
- College of Science, Health and Pharmacy, Roosevelt University, Schaumburg, IL 60173
| | - Cristina M. Furdui
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157
| | - Leslie B. Poole
- Department of Biochemistry, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157
| | - Matthew J. Schipma
- Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
- Quantitative Data Sciences Core and Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
| | - Marcelo G. Bonini
- Department of Medicine, Division of Hematology Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
- Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
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26
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Zheng Y, Yang X. Application and prospect of single-cell sequencing in cancer metastasis. Future Oncol 2022; 18:2723-2736. [PMID: 35686493 DOI: 10.2217/fon-2022-0156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Cancer metastasis is a complicated process driven by internal genetic variations and developed through interactions with the external environment. This process usually causes therapeutic resistance and results in a low survival rate. In recent years, single-cell sequencing has become a popular method for revealing the tumor evolutionary genetic lineage, intra-tumoral heterogeneity and tumor microenvironment of the metastasis process. So as to find more therapeutic targets for clinical application, the spatial transcriptomics method has become a new rising field of cancer studies, which promotes the combination between clinical medicine and molecular biology. In future prospects, more accurate and personalized treatment models will come into reality.
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Affiliation(s)
- Yue Zheng
- Department of Biochemistry & Molecular Biology, Basic Medical College, Shanxi Medical University, Taiyuan City, Shanxi Province, 030000, China
| | - Xiaofeng Yang
- Department of Urology, First Hospital of Shanxi Medical University,Taiyuan City, Shanxi Province, 030000, China
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27
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Tazawa H, Shigeyasu K, Noma K, Kagawa S, Sakurai F, Mizuguchi H, Kobayashi H, Imamura T, Fujiwara T. Tumor‐targeted fluorescence labeling systems for cancer diagnosis and treatment. Cancer Sci 2022; 113:1919-1929. [PMID: 35398956 PMCID: PMC9207361 DOI: 10.1111/cas.15369] [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: 09/23/2021] [Revised: 03/25/2022] [Accepted: 04/02/2022] [Indexed: 11/28/2022] Open
Abstract
Conventional imaging techniques are available for clinical identification of tumor sites. However, detecting metastatic tumor cells that are spreading from primary tumor sites using conventional imaging techniques remains difficult. In contrast, fluorescence‐based labeling systems are useful tools for detecting tumor cells at the single‐cell level in cancer research. The ability to detect fluorescent‐labeled tumor cells enables investigations of the biodistribution of tumor cells for the diagnosis and treatment of cancer. For example, the presence of fluorescent tumor cells in the peripheral blood of cancer patients is a predictive biomarker for early diagnosis of distant metastasis. The elimination of fluorescent tumor cells without damaging normal tissues is ideal for minimally invasive treatment of cancer. To capture fluorescent tumor cells within normal tissues, however, tumor‐specific activated target molecules are needed. This review focuses on recent advances in tumor‐targeted fluorescence labeling systems, in which indirect reporter labeling using tumor‐specific promoters is applied to fluorescence labeling of tumor cells for the diagnosis and treatment of cancer. Telomerase promoter‐dependent fluorescence labeling using replication‐competent viral vectors produces fluorescent proteins that can be used to detect and eliminate telomerase‐positive tumor cells. Tissue‐specific promoter‐dependent fluorescence labeling enables identification of specific tumor cells. Vimentin promoter‐dependent fluorescence labeling is a useful tool for identifying tumor cells that undergo epithelial–mesenchymal transition (EMT). The evaluation of tumor cells undergoing EMT is important for accurately assessing metastatic potential. Thus, tumor‐targeted fluorescence labeling systems represent novel platforms that enable the capture of tumor cells for the diagnosis and treatment of cancer.
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Affiliation(s)
- Hiroshi Tazawa
- Department of Gastroenterological Surgery Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan
- Center for Innovative Clinical Medicine Okayama University Hospital Okayama Japan
| | - Kunitoshi Shigeyasu
- Department of Gastroenterological Surgery Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan
| | - Kazuhiro Noma
- Department of Gastroenterological Surgery Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan
| | - Shunsuke Kagawa
- Department of Gastroenterological Surgery Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan
- Minimally Invasive Therapy Center Okayama University Hospital Okayama Japan
| | - Fuminori Sakurai
- Laboratory of Biochemistry and Molecular Biology Graduate School of Pharmaceutical Sciences Osaka University Osaka Japan
| | - Hiroyuki Mizuguchi
- Laboratory of Biochemistry and Molecular Biology Graduate School of Pharmaceutical Sciences Osaka University Osaka Japan
| | - Hisataka Kobayashi
- Molecular Imaging Branch Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA
| | - Takeshi Imamura
- Department of Molecular Medicine for Pathogenesis Ehime University Graduate School of Medicine Ehime Japan
| | - Toshiyoshi Fujiwara
- Department of Gastroenterological Surgery Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan
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28
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Transcriptional and post-transcriptional control of epithelial-mesenchymal plasticity: why so many regulators? Cell Mol Life Sci 2022; 79:182. [PMID: 35278142 PMCID: PMC8918127 DOI: 10.1007/s00018-022-04199-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 01/18/2022] [Accepted: 02/07/2022] [Indexed: 12/12/2022]
Abstract
The dynamic transition between epithelial-like and mesenchymal-like cell states has been a focus for extensive investigation for decades, reflective of the importance of Epithelial-Mesenchymal Transition (EMT) through development, in the adult, and the contributing role EMT has to pathologies including metastasis and fibrosis. Not surprisingly, regulation of the complex genetic networks that underlie EMT have been attributed to multiple transcription factors and microRNAs. What is surprising, however, are the sheer number of different regulators (hundreds of transcription factors and microRNAs) for which critical roles have been described. This review seeks not to collate these studies, but to provide a perspective on the fundamental question of whether it is really feasible that so many regulators play important roles and if so, what does this tell us about EMT and more generally, the genetic machinery that controls complex biological processes.
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29
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Jain AP, Sambath J, Sathe G, George IA, Pandey A, Thompson EW, Kumar P. Pan-cancer quantitation of epithelial-mesenchymal transition dynamics using parallel reaction monitoring-based targeted proteomics approach. J Transl Med 2022; 20:84. [PMID: 35148768 PMCID: PMC8832824 DOI: 10.1186/s12967-021-03227-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 12/30/2021] [Indexed: 12/31/2022] Open
Abstract
Epithelial–mesenchymal transition (EMT) is a dynamic and complex cellular process that is known to be hijacked by cancer cells to facilitate invasion, metastasis and therapeutic resistance. Several quantitative measures to assess the interplay between EMT and cancer progression are available, based on large scale genome and transcriptome data. However, these large scale multi-omics studies have repeatedly illustrated a lack of correlation in mRNA and protein abundances that may be influenced by diverse post-translational regulation. Hence, it is imperative to understand how changes in the EMT proteome are associated with the process of oncogenic transformation. To this effect, we developed a parallel reaction monitoring-based targeted proteomics method for quantifying abundances of EMT-associated proteins across cancer cell lines. Our study revealed that quantitative measurement of EMT proteome which enabled a more accurate assessment than transcriptomics data and revealed specific discrepancies against a backdrop of generally strong concordance between proteomic and transcriptomic data. We further demonstrated that changes in our EMT proteome panel might play a role in tumor transformation across cancer types. In future, this EMT panel assay has the potential to be used for clinical samples to guide treatment choices and to congregate functional information for the development and advancing novel therapeutics.
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Affiliation(s)
- Ankit P Jain
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, Karnataka, India
| | - Janani Sambath
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, Karnataka, India.,Manipal Academy of Higher Education (MAHE), Manipal, 576104, India
| | - Gajanan Sathe
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, Karnataka, India.,Manipal Academy of Higher Education (MAHE), Manipal, 576104, India.,Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029, India
| | - Irene A George
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, Karnataka, India.,Manipal Academy of Higher Education (MAHE), Manipal, 576104, India
| | - Akhilesh Pandey
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, Karnataka, India.,Manipal Academy of Higher Education (MAHE), Manipal, 576104, India.,Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029, India.,Department of Laboratory Medicine and Pathology, Centre for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Erik W Thompson
- Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, 4059, Australia. .,School-Biomedical Sciences, Translational Research Institute, Woolloongabba, QLD, 4102, Australia.
| | - Prashant Kumar
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, Karnataka, India. .,Manipal Academy of Higher Education (MAHE), Manipal, 576104, India. .,Somaiya Institute of Research and Consultancy (SIRAC), Somaiya Vidyavihar University (SVU), Vidyavihar, Mumbai, 400077, Maharashtra, India.
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30
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Lv Z, Cui B, Huang X, Feng HY, Wang T, Wang HF, Xuan YD, Li HZ, Ma X, Huang Y, Zhang X. FGL1 as a Novel Mediator and Biomarker of Malignant Progression in Clear Cell Renal Cell Carcinoma. Front Oncol 2021; 11:756843. [PMID: 34956878 PMCID: PMC8695555 DOI: 10.3389/fonc.2021.756843] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 11/22/2021] [Indexed: 12/18/2022] Open
Abstract
Clear cell renal cell carcinoma (ccRCC), which is the most prevalent renal cell carcinoma subtype, has a poor prognosis. Emerging strategies for enhancing the immune response in ccRCC therapy are currently being investigated. Fibrinogen-like Protein 1(FGL1) is a novel mechanism that tumors may use to evade the immune system by binding LAG-3 and negatively regulating T cells. In this study, we aimed at investigating the underlying mechanism of FGL1 in ccRCC, and its expression and prognostic value. We found that FGL1 was upregulated in tumor tissues and plasma specimens of ccRCC patients. High FGL1 expression predicted a poor prognosis for ccRCC patients. We also discovered that overexpression of FGL1 enhances RCC cell migration, invasion, and metastasis by activating the epithelial-to-mesenchymal transition (EMT). Consistent with these results, we identified a significant positive correlation between expression of FGL1 and EMT-related genes through tissue microarray analysis. Gene-expression analysis revealed that FGL1-deficient ccRCC cell lines had altered transcriptional output in inflammatory response, cell-cell signaling, negative regulation of T cell activation, and intracellular signal transduction. Depletion of FGL1 significantly inhibited tumor growth and lung metastasis in orthotopic xenograft mouse model. Infiltration of myeloid-derived CD11b+ and Ly6G+ immune cells in tumor microenvironment (TME) was strikingly decreased when FGL1 expression reduced. Therefore, increased FGL1 expression in ccRCC is positively correlated with poor prognosis. Mechanistically, FGL1 facilitates the EMT process and modulates TME, which promotes ccRCC progression and metastasis. Consequently, targeting FGL1 can potentially improve clinical outcome of ccRCC patients.
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Affiliation(s)
- Zheng Lv
- School of Medicine, Nankai University, Tianjin, China
| | - Bo Cui
- Medical School of Chinese PLA, Beijing, China.,Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xing Huang
- Medical School of Chinese PLA, Beijing, China.,Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Hua-Yi Feng
- Medical School of Chinese PLA, Beijing, China.,Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Tao Wang
- Medical School of Chinese PLA, Beijing, China.,Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Han-Feng Wang
- Medical School of Chinese PLA, Beijing, China.,Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yun-Dong Xuan
- Medical School of Chinese PLA, Beijing, China.,Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Hong-Zhao Li
- Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xin Ma
- Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yan Huang
- Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xu Zhang
- School of Medicine, Nankai University, Tianjin, China.,Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China
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31
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Wang Q, Karvelsson ST, Johannsson F, Vilhjalmsson AI, Hagen L, de Miranda Fonseca D, Sharma A, Slupphaug G, Rolfsson O. UDP-glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines. Mol Oncol 2021; 16:1816-1840. [PMID: 34942055 PMCID: PMC9067156 DOI: 10.1002/1878-0261.13172] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 11/04/2021] [Accepted: 12/21/2021] [Indexed: 11/07/2022] Open
Abstract
Metabolic rewiring is one of the indispensable drivers of epithelial-mesenchymal transition (EMT) involved in breast cancer metastasis. In this study, we explored the metabolic changes during spontaneous EMT in three separately established breast EMT cell models using a proteomics approach supported by metabolomic analysis. We identified common proteomic changes, including in the expression of CDH1, CDH2, VIM, LGALS1, SERPINE1, PKP3, ATP2A2, JUP, MTCH2, RPL26L1 and PLOD2. Consistently altered metabolic enzymes included: FDFT1, SORD, TSTA3 and UDP-glucose dehydrogenase (UGDH). Of these, UGDH was most prominently altered and has previously been associated with breast cancer patient survival. siRNA-mediated knockdown of UGDH resulted in delayed cell proliferation and dampened invasive potential of mesenchymal cells, and downregulated expression of the EMT transcription factor SNAI1. Metabolomic analysis revealed that siRNA-mediated knockdown of UGDH decreased intracellular glycerophosphocholine (GPC), whereas levels of acetylaspartate (NAA) increased. Finally, our data suggested that platelet-derived growth factor receptor beta (PDGFRB) signaling was activated in mesenchymal cells. siRNA-mediated knockdown of PDGFRB downregulated UGDH expression, potentially via NFkB-p65. Our results support an unexplored relationship between UGDH and GPC, both of which have previously been independently associated with breast cancer progression.
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Affiliation(s)
- Qiong Wang
- Center for Systems Biology, Biomedical Center, Faculty of Medicine, School of Health Sciences, University of Iceland, Sturlugata 8, 101, Reykjavik, Iceland
| | - Sigurdur Trausti Karvelsson
- Center for Systems Biology, Biomedical Center, Faculty of Medicine, School of Health Sciences, University of Iceland, Sturlugata 8, 101, Reykjavik, Iceland
| | - Freyr Johannsson
- Center for Systems Biology, Biomedical Center, Faculty of Medicine, School of Health Sciences, University of Iceland, Sturlugata 8, 101, Reykjavik, Iceland
| | - Arnar Ingi Vilhjalmsson
- Center for Systems Biology, Biomedical Center, Faculty of Medicine, School of Health Sciences, University of Iceland, Sturlugata 8, 101, Reykjavik, Iceland
| | - Lars Hagen
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, N-7491, Trondheim, Norway.,Clinic of Laboratory Medicine, St. Olavs hospital, Trondheim, Norway.,PROMEC Core Facility for Proteomics and Modomics, Norwegian University of Science and Technology, NTNU, and the Central Norway Regional Health Authority Norway, Norway
| | - Davi de Miranda Fonseca
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, N-7491, Trondheim, Norway.,Clinic of Laboratory Medicine, St. Olavs hospital, Trondheim, Norway.,PROMEC Core Facility for Proteomics and Modomics, Norwegian University of Science and Technology, NTNU, and the Central Norway Regional Health Authority Norway, Norway
| | - Animesh Sharma
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, N-7491, Trondheim, Norway.,Clinic of Laboratory Medicine, St. Olavs hospital, Trondheim, Norway.,PROMEC Core Facility for Proteomics and Modomics, Norwegian University of Science and Technology, NTNU, and the Central Norway Regional Health Authority Norway, Norway
| | - Geir Slupphaug
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, N-7491, Trondheim, Norway.,Clinic of Laboratory Medicine, St. Olavs hospital, Trondheim, Norway.,PROMEC Core Facility for Proteomics and Modomics, Norwegian University of Science and Technology, NTNU, and the Central Norway Regional Health Authority Norway, Norway
| | - Ottar Rolfsson
- Center for Systems Biology, Biomedical Center, Faculty of Medicine, School of Health Sciences, University of Iceland, Sturlugata 8, 101, Reykjavik, Iceland
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32
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How Lineage Tracing Studies Can Unveil Tumor Heterogeneity in Breast Cancer. Biomedicines 2021; 10:biomedicines10010003. [PMID: 35052683 PMCID: PMC8772890 DOI: 10.3390/biomedicines10010003] [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: 11/08/2021] [Revised: 12/12/2021] [Accepted: 12/17/2021] [Indexed: 11/17/2022] Open
Abstract
Lineage tracing studies have become a well-suited approach to reveal cellular hierarchies and tumor heterogeneity. Cellular heterogeneity, particularly in breast cancer, is still one of the main concerns regarding tumor progression and resistance to anti-cancer therapies. Here, we review the current knowledge about lineage tracing analyses that have contributed to an improved comprehension of the complexity of mammary tumors, highlighting how targeting different mammary epithelial cells and tracing their progeny can be useful to explore the intra- and inter-heterogeneity observed in breast cancer. In addition, we examine the strategies used to identify the cell of origin in different breast cancer subtypes and summarize how cellular plasticity plays an important role during tumorigenesis. Finally, we evaluate the clinical implications of lineage tracing studies and the challenges remaining to address tumor heterogeneity in breast cancer.
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33
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Zhao X, Hu J, Li Y, Guo M. Volumetric compression develops noise-driven single-cell heterogeneity. Proc Natl Acad Sci U S A 2021; 118:e2110550118. [PMID: 34916290 PMCID: PMC8713786 DOI: 10.1073/pnas.2110550118] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/02/2021] [Indexed: 10/19/2022] Open
Abstract
Recent studies have revealed that extensive heterogeneity of biological systems arises through various routes ranging from intracellular chromosome segregation to spatiotemporally varying biochemical stimulations. However, the contribution of physical microenvironments to single-cell heterogeneity remains largely unexplored. Here, we show that a homogeneous population of non-small-cell lung carcinoma develops into heterogeneous subpopulations upon application of a homogeneous physical compression, as shown by single-cell transcriptome profiling. The generated subpopulations stochastically gain the signature genes associated with epithelial-mesenchymal transition (EMT; VIM, CDH1, EPCAM, ZEB1, and ZEB2) and cancer stem cells (MKI67, BIRC5, and KLF4), respectively. Trajectory analysis revealed two bifurcated paths as cells evolving upon the physical compression, along each path the corresponding signature genes (epithelial or mesenchymal) gradually increase. Furthermore, we show that compression increases gene expression noise, which interplays with regulatory network architecture and thus generates differential cell-fate outcomes. The experimental observations of both single-cell sequencing and single-molecule fluorescent in situ hybridization agrees well with our computational modeling of regulatory network in the EMT process. These results demonstrate a paradigm of how mechanical stimulations impact cell-fate determination by altering transcription dynamics; moreover, we show a distinct path that the ecology and evolution of cancer interplay with their physical microenvironments from the view of mechanobiology and systems biology, with insight into the origin of single-cell heterogeneity.
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Affiliation(s)
- Xing Zhao
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138
- BGI-Shenzhen, Shenzhen 518083, China
| | - Jiliang Hu
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
| | - Yiwei Li
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China;
| | - Ming Guo
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
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34
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Zhu X, Wang X, Gong Y, Deng J. E-cadherin on epithelial-mesenchymal transition in thyroid cancer. Cancer Cell Int 2021; 21:695. [PMID: 34930256 PMCID: PMC8690896 DOI: 10.1186/s12935-021-02344-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 11/15/2021] [Indexed: 02/08/2023] Open
Abstract
Thyroid carcinoma is a common malignant tumor of endocrine system and head and neck. Recurrence, metastasis and high malignant expression after routine treatment are serious clinical problems, so it is of great significance to explore its mechanism and find action targets. Epithelial-mesenchymal transition (EMT) is associated with tumor malignancy and invasion. One key change in tumour EMT is low expression of E-cadherin. Therefore, this article reviews the expression of E-cadherin in thyroid cancers (TC), discuss the potential mechanisms involved, and outline opportunities to exploit E-cadherin on regulating the occurrence of EMT as a critical factor in cancer therapeutics.
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Affiliation(s)
- Xiaoyu Zhu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Jing'an District, Shanghai, 200040, China
| | - Xiaoping Wang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Jing'an District, Shanghai, 200040, China.
| | - Yifei Gong
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Jing'an District, Shanghai, 200040, China
| | - Junlin Deng
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Jing'an District, Shanghai, 200040, China
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35
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Lüönd F, Sugiyama N, Bill R, Bornes L, Hager C, Tang F, Santacroce N, Beisel C, Ivanek R, Bürglin T, Tiede S, van Rheenen J, Christofori G. Distinct contributions of partial and full EMT to breast cancer malignancy. Dev Cell 2021; 56:3203-3221.e11. [PMID: 34847378 DOI: 10.1016/j.devcel.2021.11.006] [Citation(s) in RCA: 209] [Impact Index Per Article: 52.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 09/13/2021] [Accepted: 11/05/2021] [Indexed: 12/13/2022]
Abstract
Epithelial-mesenchymal transition (EMT) is a transient, reversible process of cell de-differentiation where cancer cells transit between various stages of an EMT continuum, including epithelial, partial EMT, and mesenchymal cell states. We have employed Tamoxifen-inducible dual recombinase lineage tracing systems combined with live imaging and 5-cell RNA sequencing to track cancer cells undergoing partial or full EMT in the MMTV-PyMT mouse model of metastatic breast cancer. In primary tumors, cancer cells infrequently undergo EMT and mostly transition between epithelial and partial EMT states but rarely reach full EMT. Cells undergoing partial EMT contribute to lung metastasis and chemoresistance, whereas full EMT cells mostly retain a mesenchymal phenotype and fail to colonize the lungs. However, full EMT cancer cells are enriched in recurrent tumors upon chemotherapy. Hence, cancer cells in various stages of the EMT continuum differentially contribute to hallmarks of breast cancer malignancy, such as tumor invasion, metastasis, and chemoresistance.
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Affiliation(s)
- Fabiana Lüönd
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
| | - Nami Sugiyama
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
| | - Ruben Bill
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
| | - Laura Bornes
- Division of Molecular Pathology, Oncode Institute, Netherlands Cancer Institute, 1006 BE Amsterdam, the Netherlands
| | - Carolina Hager
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
| | - Fengyuan Tang
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
| | - Natascha Santacroce
- Department of Biosystems Science and Engineering, ETH Zürich, 4058 Basel, Switzerland
| | - Christian Beisel
- Department of Biosystems Science and Engineering, ETH Zürich, 4058 Basel, Switzerland
| | - Robert Ivanek
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
| | - Thomas Bürglin
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
| | - Stefanie Tiede
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
| | - Jacco van Rheenen
- Division of Molecular Pathology, Oncode Institute, Netherlands Cancer Institute, 1006 BE Amsterdam, the Netherlands
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36
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Márquez-Ortiz RA, Contreras-Zárate MJ, Tesic V, Alvarez-Eraso KLF, Kwak G, Littrell Z, Costello JC, Sreekanth V, Ormond DR, Karam SD, Kabos P, Cittelly DM. IL13Rα2 Promotes Proliferation and Outgrowth of Breast Cancer Brain Metastases. Clin Cancer Res 2021; 27:6209-6221. [PMID: 34544797 PMCID: PMC8595859 DOI: 10.1158/1078-0432.ccr-21-0361] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 08/05/2021] [Accepted: 09/16/2021] [Indexed: 01/09/2023]
Abstract
PURPOSE The survival of women with brain metastases (BM) from breast cancer remains very poor, with over 80% dying within a year of their diagnosis. Here, we define the function of IL13Rα2 in outgrowth of breast cancer brain metastases (BCBM) in vitro and in vivo, and postulate IL13Rα2 as a suitable therapeutic target for BM. EXPERIMENTAL DESIGN We performed IHC staining of IL13Rα2 in BCBM to define its prognostic value. Using inducible shRNAs in TNBC and HER2+ breast-brain metastatic models, we assessed IL13Rα2 function in vitro and in vivo. We performed RNAseq and functional studies to define the molecular mechanisms underlying IL13Rα2 function in BCBM. RESULTS High IL13Rα2 expression in BCBM predicted worse survival after BM diagnoses. IL13Rα2 was essential for cancer-cell survival, promoting proliferation while repressing invasion. IL13Rα2 KD resulted in FAK downregulation, repression of cell cycle and proliferation mediators, and upregulation of Ephrin B1 signaling. Ephrin-B1 (i) promoted invasion of BC cells in vitro, (ii) marked micrometastasis and invasive fronts in BCBM, and (iii) predicted shorter disease-free survival and BM-free survival (BMFS) in breast primary tumors known to metastasize to the brain. In experimental metastases models, which bypass early tumor invasion, downregulation of IL13Rα2 before or after tumor seeding and brain intravasation decreased BMs, suggesting that IL13Rα2 and the promotion of a proliferative phenotype is critical to BM progression. CONCLUSIONS Non-genomic phenotypic adaptations at metastatic sites are critical to BM progression and patients' prognosis. This study opens the road to use IL13Rα2 targeting as a therapeutic strategy for BM.
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Affiliation(s)
| | | | - Vesna Tesic
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | | | - Gina Kwak
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Zachary Littrell
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - James C Costello
- Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Varsha Sreekanth
- Department of Pharmacology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - D Ryan Ormond
- Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Sana D Karam
- Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Peter Kabos
- Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Diana M Cittelly
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
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37
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Modi U, Makwana P, Vasita R. Molecular insights of metastasis and cancer progression derived using 3D cancer spheroid co-culture in vitro platform. Crit Rev Oncol Hematol 2021; 168:103511. [PMID: 34740822 DOI: 10.1016/j.critrevonc.2021.103511] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 10/26/2021] [Accepted: 10/26/2021] [Indexed: 02/06/2023] Open
Abstract
The multistep metastasis process is carried out by the combinatorial effect of the stromal cells and the cancerous cells and plays vital role in the cancer progression. The scaffold/physical cues aided 3D cancer spheroid imitates the spatiotemporal organization and physiological properties of the tumor. Understanding the role of the key players in different stages of metastasis, the molecular cross-talk between the stromal cells and the cancer cells contributing in the advancement of the metastasis through 3D cancer spheroid co-culture in vitro platform is the center of discussion in the present review. This state-of-art in vitro platform utilized to study the cancer cell host defence and the role of exosomes in the cross talk leading to cancer progression has been critically examined here. 3D cancer spheroid co-culture technique is the promising next-generation in vitro approach for exploring potent treatments and personalized medicines to combat cancer metastasis leading to cancer progression.
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Affiliation(s)
- Unnati Modi
- Biomaterials & Biomimetics Laboratory, School of Life Sciences, Central University of Gujarat, Gandhinagar, India
| | - Pooja Makwana
- Biomaterials & Biomimetics Laboratory, School of Life Sciences, Central University of Gujarat, Gandhinagar, India
| | - Rajesh Vasita
- Biomaterials & Biomimetics Laboratory, School of Life Sciences, Central University of Gujarat, Gandhinagar, India.
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38
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Pan D, Jia D. Application of Single-Cell Multi-Omics in Dissecting Cancer Cell Plasticity and Tumor Heterogeneity. Front Mol Biosci 2021; 8:757024. [PMID: 34722635 PMCID: PMC8554142 DOI: 10.3389/fmolb.2021.757024] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 09/29/2021] [Indexed: 12/20/2022] Open
Abstract
Tumor heterogeneity, a hallmark of cancer, impairs the efficacy of cancer therapy and drives tumor progression. Exploring inter- and intra-tumoral heterogeneity not only provides insights into tumor development and progression, but also guides the design of personalized therapies. Previously, high-throughput sequencing techniques have been used to investigate the heterogeneity of tumor ecosystems. However, they could not provide a high-resolution landscape of cellular components in tumor ecosystem. Recently, advance in single-cell technologies has provided an unprecedented resolution to uncover the intra-tumoral heterogeneity by profiling the transcriptomes, genomes, proteomes and epigenomes of the cellular components and also their spatial distribution, which greatly accelerated the process of basic and translational cancer research. Importantly, it has been demonstrated that some cancer cells are able to transit between different states in order to adapt to the changing tumor microenvironment, which led to increased cellular plasticity and tumor heterogeneity. Understanding the molecular mechanisms driving cancer cell plasticity is critical for developing precision therapies. In this review, we summarize the recent progress in dissecting the cancer cell plasticity and tumor heterogeneity by use of single-cell multi-omics techniques.
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Affiliation(s)
- Deshen Pan
- Laboratory of Cancer Genomics and Biology, Department of Urology, and Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Deshui Jia
- Laboratory of Cancer Genomics and Biology, Department of Urology, and Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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39
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She K, Yang W, Li M, Xiong W, Zhou M. FAIM2 Promotes Non-Small Cell Lung Cancer Cell Growth and Bone Metastasis by Activating the Wnt/β-Catenin Pathway. Front Oncol 2021; 11:690142. [PMID: 34568020 PMCID: PMC8459617 DOI: 10.3389/fonc.2021.690142] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 08/09/2021] [Indexed: 12/12/2022] Open
Abstract
Aim Bone metastasis is the major reason for the poor prognosis and high mortality rate of non-small cell lung cancer (NSCLC) patients. This study explored the function and underlying mechanism of Fas apoptotic inhibitory molecule 2 (FAIM2) in the bone metastasis of NSCLC. Methods Samples of normal lung tissue and NSCLC tissue (with or without bone metastasis) were collected and analyzed for FAIM2 expression. HARA cells with FAIM2 overexpression and HARA-B4 cells with FAIM2 knockdown were tested for proliferation, migration, invasion, anoikis, and their ability to adhere to osteoblasts. Next, whether FAIM2 facilitates bone metastasis by regulating the epithelial mesenchymal transformation (EMT) process and Wnt/β-catenin signaling pathway were investigated. Finally, an in vivo model of NSCLC bone metastasis was established and used to further examine the influence of FAIM2 on bone metastasis. Results FAIM2 was highly expressed in NSCLC tissues and NSCLC tissues with bone metastasis. FAIM2 expression was positively associated with the tumor stage, lymph node metastasis, bone metastasis, and poor prognosis of NSCLC. FAIM2 upregulation promoted HARA cell proliferation, migration, and invasion, but inhibited cell apoptosis. FAIM2 knockdown in HARA-B4 cells produced the opposite effects. HARA-B4 cells showed a stronger adhesive ability to osteocytes than did HARA cells. FAIM2 was found to be related to the adhesive ability of HARA and HARA-B4 cells to osteocytes. FAIM2 facilitated bone metastasis by regulating the EMT process and Wnt/β-catenin signaling pathway. Finally, FAIM2 was found to participate in regulating NSCLC bone metastasis in vivo. Conclusions FAIM2 promoted NSCLC cell growth and bone metastasis by regulating the EMT process and Wnt/β-catenin signaling pathway. FAIM2 might be useful for diagnosing and treating NSCLC bone metastases.
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Affiliation(s)
- Kelin She
- National Health Commission (NHC) Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Cancer Research Institute, Central South University, Changsha, China.,Department of Thoracic Surgery, The Affiliated Shaoyang Hospital, Hengyang Medical School, University of South China, Shaoyang, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - Wensheng Yang
- Department of Thoracic Surgery, The Affiliated Shaoyang Hospital, Hengyang Medical School, University of South China, Shaoyang, China
| | - Mengna Li
- National Health Commission (NHC) Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Cancer Research Institute, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - Wei Xiong
- National Health Commission (NHC) Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Cancer Research Institute, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - Ming Zhou
- National Health Commission (NHC) Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Cancer Research Institute, Central South University, Changsha, China.,The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
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40
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Wu J, Huang Y, Yu C, Li X, Wang L, Hong J, Lin D, Han X, Guo G, Hu T, Huang H. The Key Gene Expression Patterns and Prognostic Factors in Malignant Transformation from Enchondroma to Chondrosarcoma. Front Oncol 2021; 11:693034. [PMID: 34568022 PMCID: PMC8461174 DOI: 10.3389/fonc.2021.693034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 08/23/2021] [Indexed: 12/11/2022] Open
Abstract
Enchondroma (EC) is a common benign bone tumor. It has the risk of malignant transformation to Chondrosarcoma (CS). However, the underlying mechanism is unclear. The gene expression profile of EC and CS was obtained from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using GEO2R. We conducted the enrichment analysis and constructed the gene interaction network using the DEGs. We found that the epithelial-mesenchymal transition (EMT) and the VEGFA-VEGF2R signaling pathway were more active in CS. The CD8+ T cell immunity was enhanced in CS I. We believed that four genes (MFAP2, GOLM1, STMN1, and HN1) were poor predictors of prognosis, while two genes (CAB39L and GAB2) indicated a good prognosis. We have revealed the mechanism in the tumor progression and identified the key genes that predicted the prognosis. This study provided new ideas for the diagnosis and treatment of EC and CS.
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Affiliation(s)
- Junqing Wu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China.,Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
| | - Yue Huang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China.,Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
| | - Chengxuan Yu
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xia Li
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China.,Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
| | - Limengmeng Wang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China.,Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
| | - Jundong Hong
- Zhejiang University City College, Hangzhou, China
| | - Daochao Lin
- Department of Orthopaedic Surgery, Shulan (Hangzhou) Hospital, Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Xiaoping Han
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China.,Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Guoji Guo
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China.,Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China.,School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China.,Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Hangzhou, China
| | - Tianye Hu
- Department of Orthopaedic Surgery, Shulan (Hangzhou) Hospital, Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - He Huang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China.,Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China.,Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
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Lovisa S. Epithelial-to-Mesenchymal Transition in Fibrosis: Concepts and Targeting Strategies. Front Pharmacol 2021; 12:737570. [PMID: 34557100 PMCID: PMC8454779 DOI: 10.3389/fphar.2021.737570] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 08/12/2021] [Indexed: 12/14/2022] Open
Abstract
The epithelial-to-mesenchymal transition (EMT), an embryonic program relaunched during wound healing and in pathological conditions such as fibrosis and cancer, continues to gain the attention of the research community, as testified by the exponential trend of publications since its discovery in the seventies. From the first description as a mesenchymal transformation, the concept of EMT has been substantially refined as an in-depth comprehension of its functional role has recently emerged thanks to the implementation of novel mouse models as well as the use of sophisticated mathematical modeling and bioinformatic analysis. Nevertheless, attempts to targeting EMT in fibrotic diseases are at their infancy and continue to pose several challenges. The aim of this mini review is to recapitulate the most recent concepts in the EMT field and to summarize the different strategies which have been exploited to target EMT in fibrotic disorders.
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Affiliation(s)
- Sara Lovisa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy.,IRCCS Humanitas Research Hospital, Rozzano (MI), Italy
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42
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Ren L, Li J, Wang C, Lou Z, Gao S, Zhao L, Wang S, Chaulagain A, Zhang M, Li X, Tang J. Single cell RNA sequencing for breast cancer: present and future. Cell Death Discov 2021; 7:104. [PMID: 33990550 PMCID: PMC8121804 DOI: 10.1038/s41420-021-00485-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 03/03/2021] [Accepted: 04/15/2021] [Indexed: 01/01/2023] Open
Abstract
Breast cancer is one of the most common malignant tumors in women. It is a heterogeneous disease related to genetic and environmental factors. Presently, the treatment of breast cancer still faces challenges due to recurrence and metastasis. The emergence of single-cell RNA sequencing (scRNA-seq) technology has brought new strategies to deeply understand the biological behaviors of breast cancer. By analyzing cell phenotypes and transcriptome differences at the single-cell level, scRNA-seq reveals the heterogeneity, dynamic growth and differentiation process of cells. This review summarizes the application of scRNA-seq technology in breast cancer research, such as in studies on cell heterogeneity, cancer cell metastasis, drug resistance, and prognosis. scRNA-seq technology is of great significance to deeply analyze the mechanism of breast cancer occurrence and development, identify new therapeutic targets and develop new therapeutic approaches for breast cancer.
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Affiliation(s)
- Lili Ren
- Department of Pathology, Harbin Medical University, Harbin, 150081, China
| | - Junyi Li
- Department of Pathology, Harbin Medical University, Harbin, 150081, China
| | - Chuhan Wang
- Department of Pathology, Harbin Medical University, Harbin, 150081, China
| | - Zheqi Lou
- Department of Pathology, Harbin Medical University, Harbin, 150081, China
| | - Shuangshu Gao
- Department of Pathology, Harbin Medical University, Harbin, 150081, China
| | - Lingyu Zhao
- Department of Pathology, Harbin Medical University, Harbin, 150081, China
| | - Shuoshuo Wang
- Department of Pathology, Harbin Medical University, Harbin, 150081, China
| | - Anita Chaulagain
- Department of Microbiology, Harbin Medical University, Harbin, 150081, China
| | - Minghui Zhang
- Department of Oncology, Chifeng City Hospital, Chifeng, 024000, China.
| | - Xiaobo Li
- Department of Pathology, Harbin Medical University, Harbin, 150081, China.
| | - Jing Tang
- Department of Pathology, Harbin Medical University, Harbin, 150081, China.
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Cai J, Cui Y, Yang J, Wang S. Epithelial-mesenchymal transition: When tumor cells meet myeloid-derived suppressor cells. Biochim Biophys Acta Rev Cancer 2021; 1876:188564. [PMID: 33974950 DOI: 10.1016/j.bbcan.2021.188564] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 05/05/2021] [Accepted: 05/05/2021] [Indexed: 12/12/2022]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous myeloid cell population characterized by protumoral functions in the tumor immune network. An increasing number of studies have focused on the biological functions of MDSCs in tumor immunity. Epithelial-mesenchymal transition (EMT) is a cellular plasticity process accompanied by a loss of epithelial phenotypes and an acquisition of mesenchymal phenotypes. In general, tumor cells that undergo EMT are more likely to invade and metastasize. Recently, extensive evidence suggests that EMT is closely related to a highly immunosuppressive environment. This review will summarize the immunosuppressive capacities of MDSC subsets and their distinct role in tumor EMT and further discuss immunotherapy for tumor EMT by targeting MDSCs.
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Affiliation(s)
- Jingshan Cai
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang, China; Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yudan Cui
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang, China; Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Jun Yang
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.
| | - Shengjun Wang
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang, China; Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China.
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44
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Tian X, Wu L, Jiang M, Zhang Z, Wu R, Miao J, Liu C, Gao S. Downregulation of GLYAT Facilitates Tumor Growth and Metastasis and Poor Clinical Outcomes Through the PI3K/AKT/Snail Pathway in Human Breast Cancer. Front Oncol 2021; 11:641399. [PMID: 33968740 PMCID: PMC8100313 DOI: 10.3389/fonc.2021.641399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 03/23/2021] [Indexed: 12/24/2022] Open
Abstract
Background The Glycine N-acyltransferase (GLYAT) gene encodes a protein that catalyzes the transfer of acyl groups from acyl CoA to glycine, resulting in acyl glycine and coenzyme A. Aberrant GLYAT expression is associated with several malignant tumors, but its clinical importance in human breast cancer (BC), has yet to be fully addressed. This study aims to evaluate the clinical function of GLYAT in BC patients. Methods GLYAT expression was determined by immune blot and immunohistochemistry in three BC cell lines and primary cancer tissues. The MDA-MB 231 cell line was used for GLYAT gene knockdown experiments while the MCF7 cell line for overexpression experiments. Colony formation experiments, soft agar experiments, and transwell assays were utilized for further inspection of cell proliferation and migration capabilities. Immunofluorescence and western blot were used to detect markers of the epithelial-mesenchymal transition (EMT) and changes in the PI3K/AKT/Snail pathway. The role of GLYAT in tumor growth and metastasis was also assessed in nude mice in vivo. Also, a correlation analysis was performed between clinicopathological features and GLYAT expression in BC patients. Results GLYAT was decreased in human BC tissues and cell lines. Functional analysis showed that knockdown of GLYAT augmented BC cell proliferation in vitro and in vivo. However, this phenomenon was reversed when GLYAT was overexpressed in the transfected cells. Moreover, downregulation of GLYAT promoted the migratory properties of BC cells, likely through the activation of PI3K/AKT/Snail signaling, which subsequently induced the EMT. IHC analysis indicated that GLYAT was decreased in human BC tissues and lower GLYAT expression was correlated with histological grade, tumor TNM stage, Ki-67 status, and poorer survival in BC patients. Furthermore, lower GLYAT expression seemed as an independent risk factor related to poor prognosis in BC patients based on Cox regression analyses. Conclusion Our findings demonstrate that downregulation of GLYAT expression in human breast cancer is correlated with EMT via the PI3K/AKT/Snail pathway and is also associated with histological grade, tumor TNM stage, Ki-67 status, and poor survival in breast cancer patients.
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Affiliation(s)
- Xin Tian
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lina Wu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Min Jiang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhenyong Zhang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Rong Wu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jianing Miao
- Key Laboratory of Shengjing Hospital, China Medical University, Shenyang, China
| | - Caigang Liu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Song Gao
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
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45
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Zhang J, Zhang X, Li Z, Wang Q, Shi Y, Jiang X, Sun X. The miR-124-3p/Neuropilin-1 Axis Contributes to the Proliferation and Metastasis of Triple-Negative Breast Cancer Cells and Co-Activates the TGF-β Pathway. Front Oncol 2021; 11:654672. [PMID: 33912463 PMCID: PMC8072051 DOI: 10.3389/fonc.2021.654672] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 03/23/2021] [Indexed: 12/18/2022] Open
Abstract
Triple-negative breast cancer (TNBC) accounts for 90% of breast cancer-associated mortality. Neuropilin-1 (NRP-1) acts as a non-tyrosine kinase receptor for several cellular signaling pathways involved in the proliferation and metastasis of cancer cells. However, the miRNAs that regulate NRP-1 expression and the underlying mechanisms in TNBC cells remain unclear. In the present study, we found that TNBC cells expressed higher levels of NRP-1 than non-TNBC cells. Stable transfectants depleted of NRP-1 were generated from two TNBC cell lines, human MDA-MB-231 and mouse 4T1 cells. NRP-1 depletion significantly suppressed the proliferation of TNBC cells by arresting the cell cycle at phase G0/G1 by upregulating p27 and downregulating cyclin E and cyclin-dependent kinase 2. NRP-1 depletion also repressed cell migration and epithelial-mesenchymal transition (EMT) by inducing the upregulation of E-cadherin and the downregulation of N-cadherin, matrix metalloproteinase (MMP)-2 and MMP-9, and reducing MMP-2 and MMP-9 activities as detected by gelatin zymography assay. By applying multiple miRNA-target prediction tools, we screened potential miRNAs with binding sites with the 3’-untranslated region of the NRP-1 gene and selected 12 miRNA candidates, among which miR-124-3p displayed the most vigorous activity to downregulate NRP-1 as validated by luciferase assay and miRNA transfection assay. By downregulating NRP-1, miR-124-3p mimics inhibited the proliferation, migration, and invasion of TNBC cells, and antagomiR-124-3p could partially abolish the effects of NRP-1 depletion. In the animal experiments, NRP-1 depletion inhibited tumorigenesis and liver metastasis of TNBC cells, while miR-124-3p mimics inhibited the growth of established TNBC tumors. In the mechanistic exploration, we revealed that NRP-1 co-interacted with transforming growth factor (TGF)-β to activate the TGF-β pathway, which regulates EMT-related molecules. In summary, the present results indicate that the miR-124-3p/NRP-1 axis contributes to the proliferation and metastasis of TNBC cells and co-activates the TGF-β pathway, suggesting that these molecules may present as potential therapeutic targets and valuable biomarkers for TNBC.
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Affiliation(s)
- Jiayang Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xuesong Zhang
- Department of General Surgery, Heilongjiang Provincial Hospital, Harbin Institute of Technology, Harbin, China
| | - Ziyi Li
- The Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qingshan Wang
- Department of General Surgery, Heilongjiang Provincial Hospital, Harbin Institute of Technology, Harbin, China.,The Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yan Shi
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xian Jiang
- The Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xueying Sun
- The Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Leggett SE, Hruska AM, Guo M, Wong IY. The epithelial-mesenchymal transition and the cytoskeleton in bioengineered systems. Cell Commun Signal 2021; 19:32. [PMID: 33691719 PMCID: PMC7945251 DOI: 10.1186/s12964-021-00713-2] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/26/2021] [Indexed: 01/04/2023] Open
Abstract
The epithelial-mesenchymal transition (EMT) is intrinsically linked to alterations of the intracellular cytoskeleton and the extracellular matrix. After EMT, cells acquire an elongated morphology with front/back polarity, which can be attributed to actin-driven protrusion formation as well as the gain of vimentin expression. Consequently, cells can deform and remodel the surrounding matrix in order to facilitate local invasion. In this review, we highlight recent bioengineering approaches to elucidate EMT and functional changes in the cytoskeleton. First, we review transitions between multicellular clusters and dispersed individuals on planar surfaces, which often exhibit coordinated behaviors driven by leader cells and EMT. Second, we consider the functional role of vimentin, which can be probed at subcellular length scales and within confined spaces. Third, we discuss the role of topographical patterning and EMT via a contact guidance like mechanism. Finally, we address how multicellular clusters disorganize and disseminate in 3D matrix. These new technologies enable controlled physical microenvironments and higher-resolution spatiotemporal measurements of EMT at the single cell level. In closing, we consider future directions for the field and outstanding questions regarding EMT and the cytoskeleton for human cancer progression. Video Abstract.
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Affiliation(s)
- Susan E Leggett
- Department of Chemical and Biological Engineering, Princeton University, William St, Princeton, NJ, 08544, USA
| | - Alex M Hruska
- School of Engineering, Center for Biomedical Engineering, and Joint Program in Cancer Biology, Brown University, 184 Hope St Box D, Providence, RI, 02912, USA
| | - Ming Guo
- Department of Mechanical Engineering, MIT, 77 Massachusetts Ave, Cambridge, MA, 02139, USA
| | - Ian Y Wong
- School of Engineering, Center for Biomedical Engineering, and Joint Program in Cancer Biology, Brown University, 184 Hope St Box D, Providence, RI, 02912, USA.
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Zhang Y, Wang D, Peng M, Tang L, Ouyang J, Xiong F, Guo C, Tang Y, Zhou Y, Liao Q, Wu X, Wang H, Yu J, Li Y, Li X, Li G, Zeng Z, Tan Y, Xiong W. Single-cell RNA sequencing in cancer research. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:81. [PMID: 33648534 PMCID: PMC7919320 DOI: 10.1186/s13046-021-01874-1] [Citation(s) in RCA: 183] [Impact Index Per Article: 45.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 02/08/2021] [Indexed: 02/06/2023]
Abstract
Single-cell RNA sequencing (scRNA-seq), a technology that analyzes transcriptomes of complex tissues at single-cell levels, can identify differential gene expression and epigenetic factors caused by mutations in unicellular genomes, as well as new cell-specific markers and cell types. scRNA-seq plays an important role in various aspects of tumor research. It reveals the heterogeneity of tumor cells and monitors the progress of tumor development, thereby preventing further cellular deterioration. Furthermore, the transcriptome analysis of immune cells in tumor tissue can be used to classify immune cells, their immune escape mechanisms and drug resistance mechanisms, and to develop effective clinical targeted therapies combined with immunotherapy. Moreover, this method enables the study of intercellular communication and the interaction of tumor cells and non-malignant cells to reveal their role in carcinogenesis. scRNA-seq provides new technical means for further development of tumor research and is expected to make significant breakthroughs in this field. This review focuses on the principles of scRNA-seq, with an emphasis on the application of scRNA-seq in tumor heterogeneity, pathogenesis, and treatment.
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Affiliation(s)
- Yijie Zhang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, The Affiliated Cancer Hospital of Xiangya School of Medicine, Hunan Cancer Hospital, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Dan Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Miao Peng
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Le Tang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Jiawei Ouyang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Fang Xiong
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Can Guo
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Yanyan Tang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, The Affiliated Cancer Hospital of Xiangya School of Medicine, Hunan Cancer Hospital, Central South University, Changsha, Hunan, China
| | - Yujuan Zhou
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, The Affiliated Cancer Hospital of Xiangya School of Medicine, Hunan Cancer Hospital, Central South University, Changsha, Hunan, China
| | - Qianjin Liao
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, The Affiliated Cancer Hospital of Xiangya School of Medicine, Hunan Cancer Hospital, Central South University, Changsha, Hunan, China
| | - Xu Wu
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, The Affiliated Cancer Hospital of Xiangya School of Medicine, Hunan Cancer Hospital, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Hui Wang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, The Affiliated Cancer Hospital of Xiangya School of Medicine, Hunan Cancer Hospital, Central South University, Changsha, Hunan, China
| | - Jianjun Yu
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, The Affiliated Cancer Hospital of Xiangya School of Medicine, Hunan Cancer Hospital, Central South University, Changsha, Hunan, China
| | - Yong Li
- Department of Medicine, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Xiaoling Li
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Guiyuan Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, The Affiliated Cancer Hospital of Xiangya School of Medicine, Hunan Cancer Hospital, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, The Affiliated Cancer Hospital of Xiangya School of Medicine, Hunan Cancer Hospital, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yixin Tan
- Department of Dermatology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, The Affiliated Cancer Hospital of Xiangya School of Medicine, Hunan Cancer Hospital, Central South University, Changsha, Hunan, China. .,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China. .,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Bocci F, Mandal S, Tejaswi T, Jolly MK. Investigating epithelial‐mesenchymal heterogeneity of tumors and circulating tumor cells with transcriptomic analysis and biophysical modeling. COMPUTATIONAL AND SYSTEMS ONCOLOGY 2021. [DOI: 10.1002/cso2.1015] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Affiliation(s)
- Federico Bocci
- Center for Theoretical Biological Physics Rice University Houston Texas USA
- NSF‐Simons Center for Multiscale Cell Fate Research University of California Irvine California USA
| | - Susmita Mandal
- Centre for BioSystems Science and Engineering Indian Institute of Science Bangalore Karnataka India
| | - Tanishq Tejaswi
- Centre for BioSystems Science and Engineering Indian Institute of Science Bangalore Karnataka India
- UG Programme Indian Institute of Science Bangalore Karnataka India
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering Indian Institute of Science Bangalore Karnataka India
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Khella CA, Mehta GA, Mehta RN, Gatza ML. Recent Advances in Integrative Multi-Omics Research in Breast and Ovarian Cancer. J Pers Med 2021; 11:149. [PMID: 33669749 PMCID: PMC7922242 DOI: 10.3390/jpm11020149] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/13/2021] [Accepted: 02/14/2021] [Indexed: 02/07/2023] Open
Abstract
The underlying molecular heterogeneity of cancer is responsible for the dynamic clinical landscape of this disease. The combination of genomic and proteomic alterations, including both inherited and acquired mutations, promotes tumor diversity and accounts for variable disease progression, therapeutic response, and clinical outcome. Recent advances in high-throughput proteogenomic profiling of tumor samples have resulted in the identification of novel oncogenic drivers, tumor suppressors, and signaling networks; biomarkers for the prediction of drug sensitivity and disease progression; and have contributed to the development of novel and more effective treatment strategies. In this review, we will focus on the impact of historical and recent advances in single platform and integrative proteogenomic studies in breast and ovarian cancer, which constitute two of the most lethal forms of cancer for women, and discuss the molecular similarities of these diseases, the impact of these findings on our understanding of tumor biology as well as the clinical applicability of these discoveries.
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Affiliation(s)
- Christen A Khella
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
| | - Gaurav A Mehta
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
| | - Rushabh N Mehta
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
| | - Michael L Gatza
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
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Guruprasad P, Lee YG, Kim KH, Ruella M. The current landscape of single-cell transcriptomics for cancer immunotherapy. J Exp Med 2021; 218:e20201574. [PMID: 33601414 PMCID: PMC7754680 DOI: 10.1084/jem.20201574] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/28/2020] [Accepted: 12/02/2020] [Indexed: 12/28/2022] Open
Abstract
Immunotherapies such as immune checkpoint blockade and adoptive cell transfer have revolutionized cancer treatment, but further progress is hindered by our limited understanding of tumor resistance mechanisms. Emerging technologies now enable the study of tumors at the single-cell level, providing unprecedented high-resolution insights into the genetic makeup of the tumor microenvironment and immune system that bulk genomics cannot fully capture. Here, we highlight the recent key findings of the use of single-cell RNA sequencing to deconvolute heterogeneous tumors and immune populations during immunotherapy. Single-cell RNA sequencing has identified new crucial factors and cellular subpopulations that either promote tumor progression or leave tumors vulnerable to immunotherapy. We anticipate that the strategic use of single-cell analytics will promote the development of the next generation of successful, rationally designed immunotherapeutics.
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Affiliation(s)
- Puneeth Guruprasad
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
- Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Yong Gu Lee
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
- Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Ki Hyun Kim
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
- Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Marco Ruella
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
- Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
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