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

Nat Mater. 2020 Jul;19(7):797-806. doi: 10.1038/s41563-020-0615-x. Epub 2020 Feb 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomechanical Phenomena
  • Cell Line, Tumor
  • Cellular Reprogramming / physiology*
  • Extracellular Matrix / physiology*
  • Female
  • Gene Expression Regulation
  • Humans
  • Mammary Glands, Human / cytology
  • Mammary Glands, Human / metabolism
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Microscopy / methods
  • Oncogenes / genetics
  • Oncogenes / physiology*
  • Pancreas / cytology
  • Sequence Analysis, RNA