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.

Reprogramming normal cells into tumour precursors requires ECM stiffness and oncogene-mediated changes of cell mechanical properties / Panciera, Tito; Citron, Anna; Di Biagio, Daniele; Battilana, Giusy; Gandin, Alessandro; Giulitti, Stefano; Forcato, Mattia; Bicciato, Silvio; Panzetta, Valeria; Fusco, Sabato; Azzolin, Luca; Totaro, Antonio; Paolo Dei Tos, Angelo; Fassan, Matteo; Vindigni, Vincenzo; Bassetto, Franco; Rosato, Antonio; Brusatin, Giovanna; Cordenonsi, Michelangelo; Piccolo, Stefano. - In: NATURE MATERIALS. - ISSN 1476-1122. - 19:(2020), pp. 797-806. [10.1038/s41563-020-0615-x]

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

Valeria Panzetta;Sabato Fusco;
2020

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.
2020
Reprogramming normal cells into tumour precursors requires ECM stiffness and oncogene-mediated changes of cell mechanical properties / Panciera, Tito; Citron, Anna; Di Biagio, Daniele; Battilana, Giusy; Gandin, Alessandro; Giulitti, Stefano; Forcato, Mattia; Bicciato, Silvio; Panzetta, Valeria; Fusco, Sabato; Azzolin, Luca; Totaro, Antonio; Paolo Dei Tos, Angelo; Fassan, Matteo; Vindigni, Vincenzo; Bassetto, Franco; Rosato, Antonio; Brusatin, Giovanna; Cordenonsi, Michelangelo; Piccolo, Stefano. - In: NATURE MATERIALS. - ISSN 1476-1122. - 19:(2020), pp. 797-806. [10.1038/s41563-020-0615-x]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/830036
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