Metabolic rewiring in skin epidermis drives tolerance to oncogenic mutations

Area of Science:

• Cell biology
• Metabolic pathways
• Oncogenesis

Background:

• Skin epithelial stem cells maintain tissue homeostasis.
• Oncogenic mutations can disrupt normal cell competition.
• Different oncogenes elicit distinct cellular responses and competition outcomes.

Purpose of the Study:

• To investigate metabolic changes in wild-type stem cells interacting with oncogenic mutant cells.
• To understand how cellular redox states influence cell competition dynamics.
• To explore the therapeutic potential of modulating metabolic states.

Main Methods:

• Single-cell resolution tracking of endogenous redox ratio (NAD(P)H/FAD) in mice over time.
• ¹³C liquid chromatography-tandem mass spectrometry to analyze metabolic flux.
• Pharmacological intervention using metformin to assess its impact on mutant phenotypes and cell competition.

Main Results:

• Both β-catenin-gain-of-function (βcatGOF) and Hras^G12V mutations induce a rapid drop in cellular redox ratios.
• The redox differential persists longer in βcatGOF compared to Hras^G12V mutant cells.
• Mutant epidermis shows increased glucose utilization via the oxidative tricarboxylic acid cycle.
• Metformin treatment reverses cell competition outcomes and inhibits downstream mutant phenotypes.

Conclusions:

• Cellular metabolic states, particularly redox balance, are critical determinants of cell competition outcomes in response to oncogenic mutations.
• Targeting metabolic pathways, such as with metformin, offers a potential therapeutic strategy to counteract oncogenic effects and restore tissue homeostasis.
• The distinct temporal dynamics of redox changes correlate with different oncogene-induced cell competition strategies.