Reprogramming normal cells into tumour precursors requires ECM stiffness and oncogenemediated changes of cell mechanical properties
Tito Panciera, Anna Citron,...,Michelangelo Cordenonsi* and Stefano Piccolo*
Email: michelangelo.cordenonsi@unipd.it; piccolo@bio.unipd.itDOI: 10.1038/s41563-020-0615-xDepartment of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
ABSTRACT
Defining the interplay between the genetic events and microenvironmental contexts necessary to initiate tumorigenesis in normal cells is a central endeavour in cancer biology. We found that receptor tyrosine kinase (RTK)–Ras oncogenes reprogram normal, freshly explanted primary mouse and human cells into tumour precursors, in a process requiring increased force transmission between oncogene-expressing cells and their surrounding extracellular matrix. Microenvironments approximating the normal softness of healthy tissues, or blunting cellular mechanotransduction, prevent oncogene-mediated cell reprogramming and tumour 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 supra-physiological extracellular-matrix rigidity they are converted into tumour-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 signalling. This work lays the groundwork for exploiting oncogenic mechanosignalling as a vulnerability at the onset of tumorigenesis, including tumour prevention strategies.中文簡介：本文報導了異常的細胞質基質硬度是致癌基因將正常細胞重新誘導為致瘤細胞的必要條件。另外一方面，致癌信號也能調節細胞的力學性質，形成細胞骨架張力，使細胞變硬，激活YAP/TAZ發揮力學轉導作用。此外，本文還報導了一種腫瘤介導因子Rac1基因，在調節細胞力學性質，將正常細胞重新誘導為腫瘤前體細胞轉變中也具有重要作用。原文連結提取碼：y3o3