Hippo Pathway Deregulation Drives Tissue Stiffness and Cancer Stem-like Cells in Lung Adenocarcinoma

Lung cancer remains the leading cause of cancer-related death due to poor treatment responses arising from tumor heterogeneity and epigenetic aberrations. Here we show that adverse prognosis associated with epigenetically silenced tumour suppressor RASSF1A is a consequence of increased extracellular matrix, tumour stiffness and metastatic dissemination in vivo and in vitro. We find that lung cancer cells with methylated RASSF1A display constitutive nuclear YAP1 and expression of prolyl4hydroxylase2 (P4HA2) into extracellular matrix that correlates with increases collagen deposition. Furthermore, we identify an epigenetic axis in tumour cells where elevated ECM impedes the intrinsic suppression of WNT signaling (via TPBG/5T4) triggering b-catenin-YAP1 activation and thus results in a cancer stem-like programming. As key drivers, we identified RASSF1A and P4HA2 mediating the ECM-dependent stemness and metastatic dissemination in vivo. Re-expression of RASSF1A or inhibition of P4HA2 activity reverse these effects and increase levels of lung differentiation markers (TTF-1, Mucin5B) in vivo and in vitro. Our study identifies an epigenetic program to cancer stemness and metastatic progression of lung adenocarcinoma and P4HA2 as potential target for uncoupling ECM signals towards cancer stemness.