Stromal integrin [alpha]11 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 [alpha]11/PDGFR[beta]-positive CAF subset displaying tumor-promoting features in BC. In the preclinical MMTV-PyMT mouse model, integrin [alpha]11 deficiency led to a drastic reduction of tumor progression and metastasis. A clear association between integrin [alpha]11 and PDGFR[beta] was found at both transcriptional and histological levels in BC specimens. High stromal integrin [alpha]11/PDGFR[beta] expression was associated with high grades and poorer clinical outcome in human BC patients. Functional assays using 5 CAF subpopulations (1 murine, 4 human) revealed that integrin [alpha]11 promotes CAF invasion and CAF-induced tumor cell invasion upon PDGF-BB stimulation. Mechanistically, the proinvasive activity of integrin [alpha]11 relies on its ability to interact with PDGFR[beta] in a ligand-dependent manner and to promote its downstream JNK activation, leading to the production of tenascin C, a proinvasive matricellular protein. Pharmacological inhibition of PDGFR[beta] and JNK impaired tumor cell invasion induced by integrin [alpha][11.sup.+] CAFs. Collectively, our study uncovers an integrin [alpha][11.sup.+] subset of protumoral CAFs that exploits the PDGFR[beta]/JNK signaling axis to promote tumor invasiveness in BC.