Format

Send to

Choose Destination
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

1
Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy.
2
Department of Industrial Engineering and INSTM, University of Padua, Padua, Italy.
3
Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
4
Interdisciplinary Research Centre on Biomaterials, CRIB, University of Naples Federico II, Naples, Italy.
5
Center for Advanced Biomaterials for Health Care IIT@CRIB, Istituto Italiano di Tecnologia, Naples, Italy.
6
Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, Padua, Italy.
7
Clinic of Plastic Surgery, Padua University Hospital, Padua, Italy.
8
Istituto Oncologico Veneto IOV-IRCCS, and Department of Surgery, Oncology and Gastroenterology, University of Padua School of Medicine, Padua, Italy.
9
Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy. michelangelo.cordenonsi@unipd.it.
10
Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy. piccolo@bio.unipd.it.
11
IFOM, The FIRC Institute of Molecular Oncology, Padua, Italy. piccolo@bio.unipd.it.

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.

PMID:
32066931
DOI:
10.1038/s41563-020-0615-x

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center