Skin epithelial stem cells correct aberrancies induced by oncogenic mutations. Oncogenes invoke different strategies of epithelial tolerance; while wild-type cells outcompete β-catenin-gain-of-function (βcatGOF) cells, Hras cells outcompete wild-type cells. Here we ask how metabolic states change as wild-type stem cells interface with mutant cells and drive different cell-competition outcomes. By tracking the endogenous redox ratio (NAD(P)H/FAD) with single-cell resolution in the same mouse over time, we discover that βcatGOF and Hras mutations, when interfaced with wild-type epidermal stem cells, lead to a rapid drop in redox ratios, indicating more oxidized cellular redox. However, the resultant redox differential persists through time in βcatGOF, whereas it is flattened rapidly in the Hrasmodel. Using C liquid chromatography-tandem mass spectrometry, we find that the βcatGOF and Hras mutant epidermis increase the fractional contribution of glucose through the oxidative tricarboxylic acid cycle. Treatment with metformin, a modifier of cytosolic redox, inhibits downstream mutant phenotypes and reverses cell-competition outcomes of both mutant models.
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