Gene expression analysis of normal mammary gland fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) from the murine breast cancer model MMTV-PyMT after perturbing the expression of Hsp90aa1 and Hsp90ab1 by RNAi

Cancers adapt proteostasis to cope with the burden of misfolded proteins, stabilize key signalling nodes and sustain their malignant behaviour. Tumour stroma is subjected to similar stresses, but how they influence its aberrant status remains unclear. We show that tumour stroma presents consistent upregulation of target genes associated to the major misfolding regulator HSP90 in cancer-associated fibroblasts (CAFs), and that HSP90α is required for CAFs to remodel the extracellular matrix (ECM) and promote cancer cell motility and growth. Mechanistically, HSP90α sustains TGFβ responses and YAP protein levels required for CAF functionality. In vivo, stromal or fibroblast-specific loss of HSP90α results in reduced ECM deposition, angiogenesis, growth and dissemination of breast tumours. Clinical analyses reveal a correlation between HSP90-dependent programs and YAP activity in CAFs, that are also associated with poor patient prognosis. Our findings uncover a link between proteostasis, mechanotransduction and generation of aggressive tumour microenvironments through HSP90α.