Cancer-associated fibroblasts actively compress cancer cells and modulate mechanotransduction

Jorge Barbazan, Carlos Pérez-González, Manuel Gómez-González, Mathieu Dedenon, Sophie Richon, Ernest Latorre, Marco Serra, Pascale Mariani, Stéphanie Descroix, Pierre Sens, Xavier Trepat () and Danijela Matic Vignjevic ()
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Jorge Barbazan: Institut Curie, PSL Research University, CNRS UMR 144
Carlos Pérez-González: Institut Curie, PSL Research University, CNRS UMR 144
Manuel Gómez-González: Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST)
Mathieu Dedenon: Institut Curie, PSL Research University, CNRS UMR 168
Sophie Richon: Institut Curie, PSL Research University, CNRS UMR 144
Ernest Latorre: Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST)
Marco Serra: Institut Curie, PSL Research University, CNRS UMR 168
Pascale Mariani: Institut Curie, Department of surgical oncology, Curie Institute
Stéphanie Descroix: Institut Curie, PSL Research University, CNRS UMR 168
Pierre Sens: Institut Curie, PSL Research University, CNRS UMR 168
Xavier Trepat: Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology (BIST)
Danijela Matic Vignjevic: Institut Curie, PSL Research University, CNRS UMR 144

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract During tumor progression, cancer-associated fibroblasts (CAFs) accumulate in tumors and produce an excessive extracellular matrix (ECM), forming a capsule that enwraps cancer cells. This capsule acts as a barrier that restricts tumor growth leading to the buildup of intratumoral pressure. Combining genetic and physical manipulations in vivo with microfabrication and force measurements in vitro, we found that the CAFs capsule is not a passive barrier but instead actively compresses cancer cells using actomyosin contractility. Abrogation of CAFs contractility in vivo leads to the dissipation of compressive forces and impairment of capsule formation. By mapping CAF force patterns in 3D, we show that compression is a CAF-intrinsic property independent of cancer cell growth. Supracellular coordination of CAFs is achieved through fibronectin cables that serve as scaffolds allowing force transmission. Cancer cells mechanosense CAF compression, resulting in an altered localization of the transcriptional regulator YAP and a decrease in proliferation. Our study unveils that the contractile capsule actively compresses cancer cells, modulates their mechanical signaling, and reorganizes tumor morphology.

Date: 2023
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DOI: 10.1038/s41467-023-42382-4

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