2. Academic Validation
  3. Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation

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

  • Signal Transduct Target Ther. 2023 Jan 11;8(1):16. doi: 10.1038/s41392-022-01227-0.
Zhaoyuan Fang # 1 2 3,  Xiangkun Han # 1 2,  Yueqing Chen # 1 2,  Xinyuan Tong 1 2,  Yun Xue 1 2,  Shun Yao 1 2,  Shijie Tang 1 2,  Yunjian Pan 4 5,  Yihua Sun 4 5,  Xue Wang 1 2,  Yujuan Jin 1 2,  Haiquan Chen 4 5,  Liang Hu 1 2,  Lijian Hui 1 2,  Lin Li 6 7 8,  Luonan Chen 9 10 11 12,  Hongbin Ji 13 14 15 16
Affiliations

Affiliations

  • 1 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 2 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, 314400, China.
  • 4 Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 5 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 6 School of Life Science and Technology, ShanghaiTech University, Shanghai, 200120, China.
  • 7 State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 8 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 9 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China. lnchen@sibs.ac.cn.
  • 10 University of Chinese Academy of Sciences, Beijing, 100049, China. lnchen@sibs.ac.cn.
  • 11 School of Life Science and Technology, ShanghaiTech University, Shanghai, 200120, China. lnchen@sibs.ac.cn.
  • 12 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, 310024, China. lnchen@sibs.ac.cn.
  • 13 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China. hbji@sibcb.ac.cn.
  • 14 University of Chinese Academy of Sciences, Beijing, 100049, China. hbji@sibcb.ac.cn.
  • 15 School of Life Science and Technology, ShanghaiTech University, Shanghai, 200120, China. hbji@sibcb.ac.cn.
  • 16 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, 310024, China. hbji@sibcb.ac.cn.
  • # Contributed equally.
PMID: 36627278 DOI: 10.1038/s41392-022-01227-0
Abstract

Lkb1 deficiency confers the Kras-mutant lung Cancer with strong plasticity and the potential for adeno-to-squamous transdifferentiation (AST). However, it remains largely unknown how Lkb1 deficiency dynamically regulates AST. Using the classical AST mouse model (Kras LSL-G12D/+;Lkb1flox/flox, 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 an essential role of the ROS-Wnt axis in dynamically orchestrating the homeostasis between adeno- and squamous-specific TF networks at the AST tipping point.

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