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bioRxiv · 10.1101/2020.11.18.388397

Fascin1 empowers YAP mechanotransduction and promotes cholangiocarcinoma development

Pocaterra, A.·Ament, C.·Ribbak, S.·Evert, M.·Chen, X.·Calvisi, D.·Dupont, S.
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Abstract

Mechanical forces control cell behavior, including cancer progression. Cells sense forces through actomyosin and YAP, but what regulators of actin mechanotransduction play relevant roles in vivo remains unclear. Here we identify the Fascin1 F-actin bundling protein as a key factor sustaining YAP activation in response to ECM mechanical cues. This is relevant in the mouse liver, where Fascin1 regulates YAP-dependent hepatocyte dedifferentiation. Moreover, Fascin1 is required in the AKT/NICD system and sufficient together with AKT to induce cholangiocarcinomas in mice, recapitulating genetic YAP requirements, and its expression in intrahepatic cholangiocarcinomas correlates with aggressiveness and poor patient prognosis. We propose that Fascin1 represents a pro-oncogenic mechanism that can be exploited during intrahepatic cholangiocarcinoma development to overcome a mechanical tumor-suppressive environment.

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Pocaterra, A., Ament, C., Ribbak, S., Evert, M., Chen, X., Calvisi, D., Dupont, S.. 2020-11-18. Fascin1 empowers YAP mechanotransduction and promotes cholangiocarcinoma development. https://doi.org/10.1101/2020.11.18.388397

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