Reprogramming normal cells into tumor precursors requires ECM stiffness and oncogene-mediated changes of cell mechanical properties

Defining the interplay between genetic events and microenvironmental contexts necessary to initiate tumorigenesis in normal cells is a central endeavor in cancer biology. We found that RTK/Ras oncogenes reprogram normal, freshly explanted primary mouse and human cells into tumor precursors, in a process requiring increased force transmission between oncogene-expressing cells and their surrounding extracellular matrix (ECM). Microenvironments approximating the normal softness of healthy tissues, or blunting cellular mechanotransduction, prevent oncogene-mediated cell reprogramming and tumor emergence. However, RTK/Ras oncogenes empower a disproportional cellular response to the mechanical properties of the cell's environment, such that when cells experience even subtle supraphysiological ECM rigidity they are converted into tumor-initiating cells. These regulations rely on YAP/TAZ mechanotransduction, and YAP/TAZ target genes account for a large fraction of the transcriptional responses downstream of oncogenic signaling. This work lays the groundwork for exploiting oncogenic mechanosignaling as vulnerability at the onset of tumorigenesis, including tumor prevention strategies.