Proteostasis control via HSP90α sustains YAP activity to drive aggressive behaviours in cancer-associated fibroblasts

Dominguez-Garcia, S.; Rodriguez, J.; Julia, M.; Coursier, D.; Perez-Lopez, C.; Carnicero, P.; Villar, A. V.; von Kriegsheim, A.; Calvo, F.

doi:10.1101/2025.04.04.647210

bioRxiv · 10.1101/2025.04.04.647210

Proteostasis control via HSP90α sustains YAP activity to drive aggressive behaviours in cancer-associated fibroblasts

Dominguez-Garcia, S.·Rodriguez, J.·Julia, M.·Coursier, D.·Perez-Lopez, C.·Carnicero, P.·Villar, A. V.·von Kriegsheim, A.·Calvo, F.

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Abstract

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 HSP90 is required for CAFs to remodel the extracellular matrix (ECM) and promote cancer cell motility and growth. Mechanistically, HSP90 sustains TGF{beta} responses and YAP protein levels required for CAF functionality. In vivo, stromal or fibroblast-specific loss of HSP90 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 HSP90.

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Dominguez-Garcia, S., Rodriguez, J., Julia, M., Coursier, D., Perez-Lopez, C., Carnicero, P., Villar, A. V., von Kriegsheim, A., Calvo, F.. 2025-04-09. Proteostasis control via HSP90α sustains YAP activity to drive aggressive behaviours in cancer-associated fibroblasts. https://doi.org/10.1101/2025.04.04.647210

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