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.
Original language | English |
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Pages (from-to) | 797-806 |
Number of pages | 10 |
Journal | Nature Materials |
Volume | 19 |
Issue number | 7 |
DOIs | |
Publication status | Published - Jul 2020 |
Keywords
- Animals
- Biomechanical Phenomena
- Cell Line, Tumor
- Cellular Reprogramming/physiology
- Extracellular Matrix/physiology
- Female
- Gene Expression Regulation
- Humans
- Mammary Glands, Human/cytology
- Mice
- Mice, Inbred Strains
- Mice, Knockout
- Microscopy/methods
- Oncogenes/genetics
- Pancreas/cytology
- Sequence Analysis, RNA