Author Response: Interplay of Opposing Fate Choices Stalls Oncogenic Growth in Murine Skin Epithelium

The study examined the activation of the HRAS oncogene in murine skin epithelium, revealing that oncogenic lesions create two cell populations: self-renewing cells at the tumor border and differentiating cells at the center, which stabilizes oncogenic growth. Using a genetically engineered mouse model and a modified CFI assay, the authors identified Rassf5 as a negative regulator of HRAS. They found that wild-type (WT) clones and HrasG12V mutant clones both tended towards a circular shape, influenced by tissue architecture. HrasG12V clones showed a dynamic of self-renewal at the edges and differentiation at the center, while WT cells near HrasG12V clones had reduced symmetric renewal. Apoptosis and senescence rates were similar between WT and HrasG12V clones. Rassf5 was confirmed to promote differentiation and affect clone composition through knockdown and overexpression experiments. The study's findings could be relevant to cancers from stratified tissues.