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

Tito Panciera, Anna Citron, Daniele Di Biagio, Giusy Battilana, Alessandro Gandin, Stefano Giulitti, Mattia Forcato, Silvio Bicciato, Valeria Panzetta, Sabato Fusco, Luca Azzolin, Antonio Totaro, Angelo Paolo Dei Tos, Matteo Fassan, Vincenzo Vindigni, Franco Bassetto, Antonio Rosato, Giovanna Brusatin, Michelangelo Cordenonsi, Stefano Piccolo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)797-806
Number of pages10
JournalNature Materials
Volume19
Issue number7
DOIs
Publication statusPublished - Jul 2020

Keywords

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

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