Loss of TET reprograms Wnt signaling through impaired demethylation to promote lung cancer development

Abstract

Significance Previous studies have identified the tumor-suppressive function of TET enzymes in hematological cancers. Given the differential mutational incidence and lacking functional validation, how TET contributes to carcinogenesis in solid tumors remains largely undefined. Here, we report that TET mutations co-occur with KRAS mutations, and such co-occurrence predicts poor survival in human LUAD. Using genetically engineered mouse models (GEMMs), we show that inactivation of TET cooperates with oncogenic KRAS to potentiate LUAD development, and that this effect is preferentially induced by augmented Wnt signaling as a consequence of impaired expression of Wnt-associated antagonists due to DNA hypermethylation. Our work reveals the tissue-specific and context-dependent roles of TET during carcinogenesis and implicates Wnt signaling as a therapeutic modality for TET -mutant lung tumors.