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作者

Fan G. Yu B. Tang L. Zhu R. Chen J. Zhu Y. Huang H. Zhou L. Liu J. Wang W. Tao Z. Zhang F. Yu S. Lu X. Cao Y. Du S. Li H. Li J. Zhang J. Ren H. Gires O. Liu H. Wang X. Qin J. Wang H.

作者单位

Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China Department of Oncology, Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine, Suzhou, China Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China De-partment of Breast-thyroid Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Shandong Province, Jinan, China Key Laboratory of Cell Differentiation and Apoptosis, Ministry of Education, Department of Pathophysiology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, Affiliated Hospital of Qingdao University, Qingdao, China Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, LMU, Munich, Germany Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Surgery, Chinese University of Hong Kong Prince of Wales Hospital, Hong, Shatin, Hong Kong CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, China

刊名

Science Translational Medicine

年份

2024

卷号

Vol.16 No.741

ISSN

1946-6234

摘要

Cancer-associated fibroblasts are abundant stromal cells in the tumor microenvironment that promote cancer progression and relapse. However, the heterogeneity and regulatory roles of CAFs underlying chemoresistance remain largely unclear. Here, we performed a single-cell analysis using high-dimensional flow cytometry analysis and identified a distinct senescence-like tetraspanin-8 myofibroblastic CAF subset, which is correlated with therapeutic resistance and poor survival in multiple cohorts...更多

Cancer-associated fibroblasts are abundant stromal cells in the tumor microenvironment that promote cancer progression and relapse. However, the heterogeneity and regulatory roles of CAFs underlying chemoresistance remain largely unclear. Here, we performed a single-cell analysis using high-dimensional flow cytometry analysis and identified a distinct senescence-like tetraspanin-8 myofibroblastic CAF subset, which is correlated with therapeutic resistance and poor survival in multiple cohorts of patients with breast cancer . TSPAN8 myCAFs potentiate the stemness of the surrounding BC cells through secretion of senescence-associated secretory phenotype –related factors IL-6 and IL-8 to counteract chemotherapy. NAD-dependent protein deacetylase sirtuin 6 reduction was responsible for the senescence-like phenotype and tumor-promoting role of TSPAN8 myCAFs. Mechanistically, TSPAN8 promoted the phosphorylation of ubiquitin E3 ligase retinoblastoma binding protein 6 at Ser by recruiting MAPK11, thereby inducing SIRT6 protein destruction. In turn, SIRT6 down-regulation up-regulated GLS1 and PYCR1, which caused TSPAN8 myCAFs to secrete aspartate and proline, and therefore proved a nutritional niche to support BC outgrowth. By demonstrating that TSPAN8SIRT6 myCAFs were tightly associated with unfavorable disease outcomes, we proposed that the combined regimen of anti-TSPAN8 antibody and SIRT6 activator MDL-800 is a promising approach to overcome chemoresistance. These findings highlight that senescence contributes to CAF heterogeneity and chemoresistance and suggest that targeting TSPAN8 myCAFs is a promising approach to circumvent chemoresistance.收起

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