美国耶鲁大学Valentina Greco等研究人员合作发现，皮肤表皮的代谢重编程驱动对致癌突变的耐受性。2025年1月6日，《自然—细胞生物学》杂志在线发表了这项成果。

研究人员表示，皮肤上皮干细胞能够纠正由致癌突变引起的异常。致癌基因采用不同的上皮耐受策略；而野生型细胞会在竞争中战胜β-连环蛋白功能增强（βcatGOF）细胞，Hras^G12V细胞则能够在竞争中战胜野生型细胞。

研究人员探讨了野生型干细胞与突变细胞相互作用时，代谢状态如何变化并驱动不同的细胞竞争结果。通过在相同小鼠中随时间跟踪内源性氧化还原比率（NAD(P)H/FAD），研究人员发现当βcatGOF和Hras^G12V突变与野生型表皮干细胞相互作用时，氧化还原比率迅速下降，表明细胞内氧化还原状态更为氧化。然而，这种氧化还原差异在βcatGOF模型中随着时间推移持续存在，而在Hras^G12V模型中则迅速趋于平坦。

通过使用¹³C液相色谱-串联质谱分析，研究人员发现βcatGOF和Hras^G12V突变的表皮增加了葡萄糖通过氧化三羧酸循环的分数贡献。使用二甲双胍（一种调节细胞质氧化还原状态的药物）治疗能够抑制下游突变表型，并逆转这两种突变模型的细胞竞争结果。

附：英文原文

Title: Metabolic rewiring in skin epidermis drives tolerance to oncogenic mutations

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

Issue&Volume: 2025-01-06

Abstract: 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, HrasG12V 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 HrasG12V 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 HrasG12Vmodel. Using 13C liquid chromatography–tandem mass spectrometry, we find that the βcatGOF and HrasG12V 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.

DOI: 10.1038/s41556-024-01574-w

Source: https://www.nature.com/articles/s41556-024-01574-w