Wild-type Skin Cells Outcompete Ras-Mutant Cells following Injury

The skin acquires somatic mutations over time, resulting in a mosaic of wild-type and mutant clones throughout the tissue. Mutations that occur within oncogenes can provide a proliferative advantage that allows mutant skin epithelial cells to outcompete neighboring wild-type cells. Given that injury and subsequent tissue repair processes have been shown to cooperate with oncogenic mutations to promote tumorigenesis, Gallini and colleagues explored the effects of injury in a mouse model of phenotypically normal, genetically mosaic skin. Administration of varying doses of tamoxifen induced the coexpression of oncogenic Hras^G12V and a fluorescent reporter in 65% or 99% of basal cells, mimicking mosaic or homogeneous skin, respectively. A full-thickness wound was introduced in the skin epithelium 3 days after tamoxifen treatment, and deep tissue imaging analysis 2 weeks after wound induction revealed a thickened epithelium only in the homogeneous Hras^G12V model, whereas mosaic Hras^G12V and wild-type control models appeared phenotypically normal. Quantification of mutant and wild-type cells in the basal stem cell layer of the epidermis over time indicated that injury selectively enhanced the proliferative capacity of wild-type cells, suggesting that, while mutant cells expanded more than wild-type cells in an uninjured context, injury repair eliminated this proliferative advantage because mutant cells could not respond as well as wild-type cells to signals mediating epithelial regrowth. Indeed, injury increased epithelial and fibroblast expression of ligands for epidermal growth factor receptor (EGFR), and pharmacologic or genetic inhibition of EGFR signaling prevented wild-type cell expansion and restored the proliferative advantage of mutant cells during injury repair. Moreover, promoting wild-type cell proliferation via genetic knockout of the cell-cycle inhibitor Cdkn1a was sufficient to counter the enhanced proliferation of mutant cells in an uninjured state. Together, these findings highlight the role of wild-type epithelial cells in preventing the expansion of oncogenic mutant clones in response to injury repair processes.

Gallini S, Annusver K, Rahman NT, Gonzalez DG, Yun S, Matte-Martone C, et al. Injury prevents Ras mutant cell expansion in mosaic skin. Nature 2023;619:167–75.

Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.