An Extracellular Matrix–Producing Subset of Cancer-Associated Fibroblasts Drives Chemoresistance in Breast Cancer via SRC Activation and G0S2 Upregulation
Year: 2025
Type: article
Abstract: Chemotherapy resistance remains a major hurdle for treating patients with triple-negative breast cancer (TNBC). Although cancer-associated fibroblasts (CAF) as an overall population have been shown to modulate treatment response, innovative approaches are required to decipher which and how distinct CAF populations drive chemoresistance. In this study, by combining analysis of data from patients with TNBC with ex vivo modeling using tumor-on-chip technology, we identified a specific CAF population, the extracellular matrix-producing myofibroblasts (ECM-myCAF), that mediated resistance to chemotherapy. The proportion of ECM-myCAFs decreased after chemotherapy in chemosensitive patients but remained unchanged in chemoresistant patients. In tumor-on-chip models, primary ECM-myCAFs promoted TNBC cell survival under chemotherapy treatment. Single-cell RNA sequencing, advanced cell imaging, and functional assays showed that ECM-myCAFs activated SRC kinases in TNBC cells, likely through secreted factors, and upregulated the apoptosis regulator G0-G1 switch 2 (G0S2). SRC inhibition or G0S2 silencing completely abolished TNBC cell chemoresistance driven by ECM-myCAFs. Altogether, this work reveals the unique role of the specific ECM-myCAF population and identifies G0S2 as a key player in chemoresistance in TNBC. SIGNIFICANCE: Integration of patient data with ex vivo tumor-on-chip modeling identifies an extracellular matrix-producing myofibroblast population that contributes to chemoresistance and can be targeted to improve outcomes in triple-negative breast cancer.
Source: Cancer Research
Institutions: Centre National de la Recherche Scientifique, Inserm, Université Paris Sciences et Lettres, La Ligue Contre le Cancer, Chimie et Biologie de la Cellule, Institut Curie, University of Rome Tor Vergata, Institut Pierre-Gilles de Gennes pour la Microfluidique, Physique des Cellules et Cancers, Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines, Université Paris Cité
Language: English
Topic: Cancer Cells and Metastasis
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Fondation ARC pour la Recherche sur le Cancer, Fondation de France, Institut National Du Cancer, Horizon 2020 Framework Programme, HORIZON EUROPE Framework Programme
Awards: MAppinG adaptatioN Of tripLe negative breast cancer microenvironments to ImmunotherApy, G278937460, «TME ON CHIP» Tumor on chip for improved patient care, G3259945745, G4706853027, G4954510238, G5535373201, G5820380967, G5908295196, Institut des cancers des femmes, Targeting Cancer-Associated Fibroblasts to tackle metastases and resistance to treatment in Triple Negative Breast Cancer, Cancer and lymphoid stroma (CALYS): deciphering stromal heterogeneity – identity, origins and functions – in solid and lymphoid cancers, G6869949044, Deciphering the impact of STROMA in high grade serous Epithelial Ovarian Carcinomas, ChemoCAFs : Chemotherapeutic response of fibroblast ecosystems in human breast cancer at single cell resolution, G7217540724, G7274551484, Spatial and molecular characterization of stromal heterogeneity and plasticity in cancer, G8144498861, G8999482646
OpenAlex ID: W4416155247