Mechano-signaling of prostate tumor initiating cells facilitates their tropism to stiff metastatic niche

Abstract

AbstractAnalysis of clinical datasets indicate that cancer stem-like cells/tumor-initiating cells (CSCs/TICs) derived from prostate cancer (PCa) patients display an elevated expression of genes for cell-matrix interactions, cell adhesion proteins and of the putative mechanotransducer TAZ. Here we combined measurements on the cellular mechano-responses to matrix stiffness, including cell-generated forces, zebrafish and PDX-derived organoid models, to show that mechanotransduction serves as a key determinant for PCa CSC maintenance during metastatic onset. The β1-integrin-ILK-CDC42-N-Wasp dependent cytoskeletal tension and TAZ nucleus-translocation mediate this mechano-signaling axis. As a result, expression of the stemness genes NANOG and OCT4 are induced, leading to metastatic tumor initiation. It is further demonstrated that pharmaceutical perturbation of this mechano-signaling using a novel YAP/TAZ inhibitor K975 constrains PCa metastasis in zebrafish, and development of PDX-derived organoids. Our data highlights the essential role of mechanotransduction in PCa aggressiveness, thereby underlying this pathway as a therapeutic target for future studies.