2. Academic Validation
  3. TSPAN8+ myofibroblastic cancer-associated fibroblasts promote chemoresistance in patients with breast cancer

TSPAN8+ myofibroblastic cancer-associated fibroblasts promote chemoresistance in patients with breast cancer

  • Sci Transl Med. 2024 Apr 3;16(741):eadj5705. doi: 10.1126/scitranslmed.adj5705.
Guangjian Fan 1,  Bo Yu 2,  Lei Tang 3,  Rongxuan Zhu 1,  Jianhua Chen 2,  Ying Zhu 1,  He Huang 4,  Liying Zhou 4,  Jun Liu 5,  Wei Wang 5,  Zhonghua Tao 2,  Fengchun Zhang 3,  Siwei Yu 1,  Xiaoqing Lu 6,  Yuan Cao 1,  Shaoqian Du 1,  Huihui Li 7,  Junjian Li 1,  Jian Zhang 8,  He Ren 9,  Olivier Gires 10,  Haikun Liu 11,  Xin Wang 12,  Jun Qin 13,  Hongxia Wang 1 2
Affiliations

Affiliations

  • 1 Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
  • 2 Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 3 Department of Oncology, Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine, Suzhou 215000, China.
  • 4 Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200243, China.
  • 5 Department of Breast-thyroid Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
  • 6 Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan 030013, China.
  • 7 Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province 271016, China.
  • 8 Key Laboratory of Cell Differentiation and Apoptosis, Ministry of Education, Department of Pathophysiology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 342500, China.
  • 9 Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, Affiliated Hospital of Qingdao University, Qingdao 266000, China.
  • 10 Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, LMU, Munich 80336, Germany.
  • 11 Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
  • 12 Department of Surgery, Chinese University of Hong Kong Prince of Wales Hospital, Shatin, Hong Kong SAR 999077, China.
  • 13 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 200031, China.
PMID: 38569015 DOI: 10.1126/scitranslmed.adj5705
Abstract

Cancer-associated fibroblasts (CAFs) 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 (TSPAN8)+ myofibroblastic CAF (myCAF) subset, which is correlated with therapeutic resistance and poor survival in multiple cohorts of patients with breast Cancer (BC). TSPAN8+ myCAFs potentiate the stemness of the surrounding BC cells through secretion of senescence-associated secretory phenotype (SASP)-related factors IL-6 and IL-8 to counteract chemotherapy. NAD-dependent protein deacetylase Sirtuin 6 (SIRT6) 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 (RBBP6) at Ser772 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 TSPAN8+SIRT6low 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.

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