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

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...

Celý popis

Uloženo v:

Podrobná bibliografie
Vydáno v:	Nature materials Ročník 19; číslo 7; s. 797 - 806
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 01.07.2020 Nature Publishing Group
Témata:	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
On-line přístup:	Získat plný text
Tagy:	Přidat tag Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!

Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Co-last authors
ISSN:	1476-1122 1476-4660 1476-4660
DOI:	10.1038/s41563-020-0615-x