Oncogenic lesions are surprisingly common in morphologically and functionally normal human skin, however, the cellular and molecular mechanisms that suppress their cancer-driving potential to maintain tissue homeostasis are unknown. By employing assays for direct and quantitative assessment of cell fate choices in vivo , we show that oncogenic activation of PI3K/AKT, the most commonly activated oncogenic pathway in cancer, promotes differentiation and cell-cycle exit of epidermal progenitors. As a result, oncogenic PI3K/AKT activated epidermis exhibits growth disadvantage even though its cells are more proliferative. To uncover the underlying mechanism behind oncogene-induced differentiation, we conduct a series of genetic screens in vivo , and identify an AKT substrate SH3RF1 as a specific promoter of epidermal differentiation that has no effect on proliferation. Our study provides evidence for a direct, cell autonomous mechanism that can suppresses progenitor cell renewal and block clonal expansion of epidermal cells bearing a common and activating mutation in Pik3ca.

Skin epithelium can accumulate a high burden of oncogenic mutations without morphological or functional consequences. To investigate the mechanism of oncogenic tolerance, we induced HrasG12V in single murine epidermal cells and followed them long term. We observed that HrasG12V promotes an early and transient clonal expansion driven by increased progenitor renewal that is replaced with an increase in progenitor differentiation leading to reduced growth. We attribute this dynamic effect to emergence of two populations within oncogenic clones: renewing progenitors along the edge and differentiating ones within the central core. As clone expansion is accompanied by progressive enlargement of the core and diminishment of the edge compartment, the intraclonal competition between the two populations results in stabilized oncogenic growth. To identify the molecular mechanism of HrasG12V-driven differentiation, we screened known Ras-effector in vivo and identified Rassf5 as a novel regulator of progenitor fate choice that is necessary and sufficient for oncogene-specific differentiation.

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