Injury prevents Ras mutant cell expansion in mosaic skin

Healthy skin is a tapestry of wild-type and mutant clones. Although injury can cooperate with Ras mutations to promote tumorigenesis, the consequences in genetically mosaic skin are unknown. Here, we show that wild-type cells suppress oncogenic Ras-induced aberrant growth after injury. While HrasG12V/+ and KrasG12D/+ cells outcompete wild-type cells in uninjured, mosaic tissue, their expansion is prevented after injury due 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 by both drug and genetic approaches diminished the proportion of dividing wild-type cells after injury, leading to the expansion of HrasG12V/+ cells. Increased wild-type cell proliferation through a global loss of the cell cycle inhibitor p21 counteracted the expansion of HrasG12V/+ cells even without injury. Thus, injury plays an unanticipated role in switching the competitive balance between oncogenic and wild-type cells in genetically mosaic skin. Interfollicular epidermis of mice ear punches, either injured or uninjured, in wild-type or HRASG12V/+ background.