Injury prevents Ras mutant cell expansion in mosaic skin

Sara Gallini, Karl Annusver, Nur-Taz Rahman, David G. Gonzalez, Sangwon Yun, Catherine Matte-Martone, Tianchi Xin, Elizabeth Lathrop, Kathleen C. Suozzi, Maria Kasper () and Valentina Greco ()
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Sara Gallini: Yale School of Medicine
Karl Annusver: Karolinska Institutet
Nur-Taz Rahman: Bioinformatics Support Program, Cushing/Whitney Medical Library, Yale School of Medicine
David G. Gonzalez: Yale School of Medicine
Sangwon Yun: Yale School of Medicine
Catherine Matte-Martone: Yale School of Medicine
Tianchi Xin: Yale School of Medicine
Elizabeth Lathrop: Yale School of Medicine
Kathleen C. Suozzi: Yale School of Medicine
Maria Kasper: Karolinska Institutet
Valentina Greco: Yale School of Medicine

Nature, 2023, vol. 619, issue 7968, 167-175

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06198-y

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