Differential Metabolic Adaptations Define Responses of Winner and Loser Oncogenic Mutant Stem Cells in Skin Epidermis In Vivo

November 2022 in “ bioRxiv (Cold Spring Harbor Laboratory) ”

Anupama Hemalatha, Zongyu Li, Karen Tai, David G. Gonzalez, Elizabeth Lathrop, Daniel A. Gil, Catherine Matte-Martone, Smirthy Ganesan, Sangwon Yun, Lauren E. Gonzalez, Melissa C. Skala, Rachel J. Perry, Valentina Greco

skin epidermis stem cells oncogenic mutant β-catenin-Gain-of-Function Hras G12V redox ratios tricarboxylic acid cycle glycolytic flux skin mutant cells TCA cycle Krebs cycle

TLDR Mutant stem cells adapt their metabolism differently to outcompete normal cells in the skin.

The study investigated how metabolic states change in wild-type and mutant skin epithelial stem cells, focusing on β-catenin-Gain-of-Function (βcatGOF) and HrasG12V mutations. It was found that wild-type cells outcompeted βcatGOF mutants, while HrasG12V mutants outcompeted wild-type cells. Using live-imaging to track redox ratios and mass spectrometry, researchers observed that both mutations caused a drop in redox ratios, but "winner" cells in each model quickly recovered. Both mutants increased oxidative tricarboxylic acid cycle flux, but differed in glycolytic flux modulation. This revealed distinct metabolic adaptations that define cell competition outcomes in vivo.

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