Stromal integrin alpha11 regulates PDGFR-beta signaling and promotes breast cancer progression.

Cancer-associated fibroblasts (CAFs) are key actors in modulating the progression of many solid tumors such as breast cancer (BC). Herein, we identify an integrin alpha11/PDGFRbeta+ CAF subset displaying tumor-promoting features in BC. In the preclinical MMTV-PyMT mouse model, integrin alpha11-deficiency led to a drastic reduction of tumor progression and metastasis. A clear association between integrin alpha11 and PDGFRbeta was found at both transcriptional and histological levels in BC specimens. High stromal integrin alpha11/PDGFRbeta expression was associated with high grades and poorer clinical outcome in human BC patients. Functional assays using five CAF subpopulations (one murine, four human) revealed that integrin alpha11 promotes CAF invasion and CAF-induced tumor cell invasion upon PDGF-BB stimulation. Mechanistically, integrin alpha11 pro-invasive activity relies on its ability to interact with PDGFRbeta in a ligand-dependent manner and to promote its downstream JNK activation, leading to the production of tenascin C, a pro-invasive matricellular protein. Pharmacological inhibition of PDGFRbeta and JNK impaired tumor cell invasion induced by integrin alpha11-positive CAFs. Collectively, our study uncovers an integrin alpha11-positive subset of pro-tumoral CAFs that exploits PDGFRbeta/JNK signalling axis to promote tumor invasiveness in BC.