Fascin1 empowers YAP mechanotransduction and promotes cholangiocarcinoma development

Arianna Pocaterra,Gloria Scattolin,Silvia Ribback,Matthias Evert,Patrizia Romani,Sirio Dupont,Xin Chen,Cindy Ament,Diego F. Calvisi

doi:10.1038/s42003-021-02286-9

Abstract

Mechanical forces control cell behavior, including cancer progression. Cells sense forces through actomyosin to activate YAP. However, the regulators of F-actin dynamics playing relevant roles during mechanostransduction in vitro and in vivo remain poorly characterized. Here we identify the Fascin1 F-actin bundling protein as a factor that sustains YAP activation in response to ECM mechanical cues. This is conserved in the mouse liver, where Fascin1 regulates YAP-dependent phenotypes, and in human cholangiocarcinoma cell lines. Moreover, this is relevant for liver tumorigenesis, because Fascin1 is required in the AKT/NICD cholangiocarcinogenesis model and it is sufficient, together with AKT, to induce cholangiocellular lesions in mice, recapitulating genetic YAP requirements. In support of these findings, Fascin1 expression in human intrahepatic cholangiocarcinomas strongly correlates with 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.

Highlights

Mechanical forces control cell behavior, including cancer progression
Evidence for CAPZ regulating the balance between branched and bundled Factin mainly comes from studies on cell migration, and whether this is relevant for mechanotransduction remains unexplored
Led by the known function of CAPZ in shifting the balance between actin bundled vs. branched structures during cell migration[29,31], we identify Ena/VASP and Fascin[1] proteins as required for YAP activity in response to extracellular matrix (ECM) stiffness

Summary

Introduction

Mechanical forces control cell behavior, including cancer progression. Cells sense forces through actomyosin to activate YAP. We identify the Fascin[1] F-actin bundling protein as a factor that sustains YAP activation in response to ECM mechanical cues This is conserved in the mouse liver, where Fascin[1] regulates YAP-dependent phenotypes, and in human cholangiocarcinoma cell lines. This is relevant for liver tumorigenesis, because Fascin[1] is required in the AKT/NICD cholangiocarcinogenesis model and it is sufficient, together with AKT, to induce cholangiocellular lesions in mice, recapitulating genetic YAP requirements. What actin-regulatory factors are important for ECM mechanotransduction and are relevant to drive YAP/TAZ activity in tissues and for cancer development, remains poorly defined. A similar function of CAPZ has been observed in yeast, indicating this is not restricted to cell protrusions and cell migration[34]

Methods

Results

Conclusion