Injury prevents Ras mutant cell expansion in mosaic skin
- PMID: 37344586
- PMCID: PMC10322723
- DOI: 10.1038/s41586-023-06198-y
Injury prevents Ras mutant cell expansion in mosaic skin
Abstract
Healthy skin is a mosaic of wild-type and mutant clones1,2. Although injury can cooperate with mutated Ras family proteins to promote tumorigenesis3-12, the consequences in genetically mosaic skin are unknown. Here we show that after injury, wild-type cells suppress aberrant growth induced by oncogenic Ras. HrasG12V/+ and KrasG12D/+ cells outcompete wild-type cells in uninjured, mosaic tissue but their expansion is prevented after injury owing to an increase in the fraction of proliferating wild-type cells. Mechanistically, we show that, unlike HrasG12V/+ cells, wild-type cells respond to autocrine and paracrine secretion of EGFR ligands, and this differential activation of the EGFR pathway explains the competitive switch during injury repair. Inhibition of EGFR signalling via drug or genetic approaches diminishes the proportion of dividing wild-type cells after injury, leading to the expansion of HrasG12V/+ cells. Increased proliferation of wild-type cells via constitutive loss of the cell cycle inhibitor p21 counteracts the expansion of HrasG12V/+ cells even in the absence of injury. Thus, injury has a role in switching the competitive balance between oncogenic and wild-type cells in genetically mosaic skin.
© 2023. The Author(s).
Conflict of interest statement
The authors declare no competing interests.
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Comment in
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Wild-type Skin Cells Outcompete Ras-Mutant Cells following Injury.Cancer Discov. 2023 Sep 6;13(9):1956. doi: 10.1158/2159-8290.CD-RW2023-106. Cancer Discov. 2023. PMID: 37417827
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References
-
- Fowler JC, et al. Selection of oncogenic mutant clones in normal human skin varies with body site. Cancer Discov. 2021;11:340–361. doi: 10.1158/2159-8290.CD-20-1092. - DOI - PMC - PubMed
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