Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation

作者：Zhaoyuan Fang, Xiangkun Han, Yueqing Chen, Xinyuan Tong, Yun Xue, Shun Yao, Shijie Tang, Yunjian Pan, Yihua Sun, Xue Wang, Yujuan Jin, Haiquan Chen, Liang Hu, Lijian Hui, Lin Li, Luonan Chen, Hongbin Ji · 发表于：Signal Transduction and Targeted Therapy · 年份：2023 · DOI：10.1038/s41392-022-01227-0 · 被引用次数：37 · 研究领域：FOXO transcription factor regulation、Epigenetics and DNA Methylation、Cancer Cells and Metastasis

, KL), we here comprehensively analyze the temporal transcriptomic dynamics of lung tumors at different stages by dynamic network biomarker (DNB) and identify the tipping point at which the Wnt signaling is abruptly suppressed by the excessive accumulation of reactive oxygen species (ROS) through its downstream effector FOXO3A. Bidirectional genetic perturbation of the Wnt pathway using two different Ctnnb1 conditional knockout mouse strains confirms its essential role in the negative regulation of AST. Importantly, pharmacological activation of the Wnt pathway before but not after the tipping point inhibits squamous transdifferentiation, highlighting the irreversibility of AST after crossing the tipping point. Through comparative transcriptomic analyses of mouse and human tumors, we find that the lineage-specific transcription factors (TFs) of adenocarcinoma and squamous cell carcinoma form a "Yin-Yang" counteracting network. Interestingly, inactivation of the Wnt pathway preferentially suppresses the adenomatous lineage TF network and thus disrupts the "Yin-Yang" homeostasis to lean towards the squamous lineage, whereas ectopic expression of NKX2-1, an adenomatous lineage TF, significantly dampens such phenotypic transition accelerated by the Wnt pathway inactivation. The negative correlation between the Wnt pathway and AST is further observed in a large cohort of human lung adenosquamous carcinoma. Collectively, our study identifies the tipping point of AST and highlights ...