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

• Published in: Nature materials Vol. 19; no. 7; pp. 797 - 806
• Main Authors: 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, Dei Tos, Angelo Paolo, Fassan, Matteo, Vindigni, Vincenzo, Bassetto, Franco, Rosato, Antonio, Brusatin, Giovanna, Cordenonsi, Michelangelo, Piccolo, Stefano
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2020; Nature Publishing Group
• Subjects: 631/67/327; 631/80/79/750; Animals; Biomaterials; Biomechanical Phenomena; Cell Line, Tumor; Cellular Reprogramming - physiology; Chemistry and Materials Science; Condensed Matter Physics; Empowerment; Extracellular Matrix - physiology; Female; Gene Expression Regulation; Humans; Kinases; Mammary Glands, Human - cytology; Mammary Glands, Human - metabolism; Materials Science; Mechanical properties; Mice; Mice, Inbred Strains; Mice, Knockout; Microenvironments; Microscopy - methods; Nanotechnology; Oncogenes - genetics; Oncogenes - physiology; Optical and Electronic Materials; Pancreas - cytology; Precursors; Receptors; Rigidity; Sequence Analysis, RNA; Signaling; Softness; Stiffness; Tumorigenesis; Tumors; Tyrosine
• ISSN: 1476-1122; 1476-4660; 1476-4660
• DOI: 10.1038/s41563-020-0615-x

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. Receptor tyrosine kinase (RTK)–Ras oncogenes have now been shown to reprogram normal primary human and mouse cells into tumour precursors by empowering cellular mechanotransduction, in a process requiring permissive extracellular-matrix rigidity and intracellular YAP/TAZ/Rac mechanical signalling sustained by activated oncogenes.