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Nat Mater. 2020 Feb 17. doi: 10.1038/s41563-020-0615-x. [Epub ahead of print]

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

Author information

Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy.
Department of Industrial Engineering and INSTM, University of Padua, Padua, Italy.
Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Interdisciplinary Research Centre on Biomaterials, CRIB, University of Naples Federico II, Naples, Italy.
Center for Advanced Biomaterials for Health Care IIT@CRIB, Istituto Italiano di Tecnologia, Naples, Italy.
Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, Padua, Italy.
Clinic of Plastic Surgery, Padua University Hospital, Padua, Italy.
Istituto Oncologico Veneto IOV-IRCCS, and Department of Surgery, Oncology and Gastroenterology, University of Padua School of Medicine, Padua, Italy.
Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy.
Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy.
IFOM, The FIRC Institute of Molecular Oncology, Padua, Italy.


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.


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