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

Oncogenic imbalance of DNA methylation is well-recognized in cancer development. Ten-eleven translocation (TET) family of dioxygenases, which facilitate DNA demethylation, are frequently dysregulated in cancers. How such dysregulation contributes to tumorigenesis remains poorly understood, especially in solid tumors which present infrequent mutational incidence of TET genes. Here we identify TET mutations in 7.4% of human lung adenocarcinoma (LUAD), which frequently co-occur with oncogenic KRAS mutations, and this co-occurrence is predictive of poor survival in LUAD patients. Using autochthonous mouse model of KrasG12D-driven LUAD, we show that individual or combinational loss of Tet genes markedly promotes tumor development. In this Kras-mutant and Tet-deficient model, pre-malignant lung epithelium undergoes neoplastic reprogramming of DNA methylation and transcription, with a particular impact on Wnt signaling. Among the Wnt-associated components that undergo reprogramming, multiple canonical Wnt antagonizing genes present impaired expression arising from elevated DNA methylation, triggering aberrant activation of Wnt signaling. These impairments can be largely reversed upon the restoration of TET activity. Correspondingly, genetic depletion of ß-catenin, the transcriptional effector of Wnt signaling, substantially reverts the malignant progression of Tet-deficient LUAD. These findings reveal TET enzymes as critical epigenetic barriers against lung tumorigenesis and highlight the therapeutic vulnerability of TET-mutant lung cancer through targeting Wnt signaling. Overall design: Low-input RNA-seq and low-input WGBS were performed on mouse pre-malignant lung epithelial cells in the setting of mutant Kras to compare gene expression and DNA methylation differences between Tet-deficient and wild type samples. Bulk RNA-seq and Bulk TAPS were performed on KrasG12D/+; Tet-deficient (KT) LUAD cell lines derived from tumor-bearing mouse lung tissues following constitutive expression of Tet2CD or Tet2HD to examine alterations in gene expression and DNA methylation upon re-introduction of TET catalytic activity.