In colon cancer cells, fascin1 functions as a mechanosensor that transforms adherens junction mechanotransduction

Abstract

Almost one-third of colorectal carcinomas (CRCs) arise from sessile serrated lesions (SSLs) which have > 90% rate of BRAFV600E mutations. Serrated pathway CRCs are aggressive, have poor prognosis and lack treatment options. The pro-metastasis actin-bundling protein fascin1 is absent from the normal colon but is a marker of SSLs and is differentially expressed between serrated pathway and conventional CRCs.However, its function in serrated pathway carcinogenesis has not been directly evaluated. We identify for the first time, the novel function of fascin1 in remodeling cell-cell adhesions in BRAFV600E-mutated CRC cells. Our study shows in BRAFV600E-mutated CRC cells fascin1 remodels adherens junction (AJ) mechanotransduction to directly activate oncogenic Wnt signaling which drives primary and secondary tumor growth in mice. More importantly, fascin1 AJ remodeling function contributes to the hybrid epithelial-mesenchymal (E/M) state and promotes collective cell migration. We identify fascin1 as a driver and a novel therapeutic target in serrated/BRAFV600E-mutated CRCs.