Interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium

Skin epithelium can accumulate a high burden of oncogenic mutations without morphological or functional consequences. To investigate the mechanism of oncogenic tolerance, we induced Hras G(12V) in single murine epidermal cells and followed them long term. We observed that Hras G(12V) 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 Hras G(12V) -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.

Automated summary

The study investigates how skin epithelium can accumulate oncogenic mutations without obvious consequences by inducing Hras G(12V) in single murine epidermal cells. It is found that the dynamic effect of Hras G(12V) on clonal expansion is attributed to the emergence of renewing progenitors and differentiating ones within the oncogenic clones, leading to stabilized oncogenic growth. Further research identifies Rassf5 as a novel regulator necessary for oncogene-specific differentiation.