Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumorigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC-mutant intestinal organoids to promote stemness, and leads to adenocarcinoma formation in vivo via decreasing intracellular α-ketoglutarate (αKG) levels. αKG supplementation is sufficient to rescue low-glutamine-induced stemness and Wnt hyperactivation. Mechanistically, we found that αKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using organoids derived from patients with CRC and several in vivo CRC tumor models, we show that αKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumor growth and extending survival. Together, our results reveal how the metabolic microenvironment impacts Wnt signaling and identify αKG as a potent antineoplastic metabolite for potential differentiation therapy for patients with CRC.

基因驱动的 Wnt 通路失调对于结直肠癌 (CRC) 肿瘤发生至关重要，但还不够。在这里，我们发现环境谷氨酰胺限制进一步增强了APC突变型肠类器官中的 Wnt 信号传导，从而促进干细胞性，并通过降低细胞内 α-酮戊二酸 (αKG) 水平导致体内腺癌形成。补充 αKG 足以挽救低谷氨酰胺引起的干细胞性和 Wnt 过度激活。从机制上讲，我们发现αKG促进DNA和组蛋白H3K4me3的低甲基化，分别导致分化相关基因的上调和Wnt靶基因的下调。使用源自 CRC 患者的类器官和几种体内 CRC 肿瘤模型，我们发现补充 αKG 可以抑制 Wnt 信号传导并促进细胞分化，从而显着限制肿瘤生长并延长生存期。总之，我们的结果揭示了代谢微环境如何影响 Wnt 信号传导，并确定 αKG 作为一种有效的抗肿瘤代谢物，可用于 CRC 患者的潜在分化治疗。