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

doi:10.1038/s41392-022-01227-0

	Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation
	Fang, Zhaoyuan 1,2,3; Han, Xiangkun 1,2; Chen, Yueqing 1,2; Tong, Xinyuan 1,2; Xue, Yun 1,2; Yao, Shun 1,2; Tang, Shijie 1,2; Pan, Yunjian 4,5; Sun, Yihua 4,5; Wang, Xue 1,2; Jin, Yujuan 1,2; Chen, Haiquan 4,5; Hu, Liang 1,2; Hui, Lijian 1,2; Li, Lin6,7,8 ; Chen, Luonan1,2,6,8 ; Ji, Hongbin1,2,6,8
	2023-12-01
发表期刊	SIGNAL TRANSDUCTION AND TARGETED THERAPY;
ISSN	2095-9907
EISSN	2059-3635
卷号	8 期号:1
DOI	10.1038/s41392-022-01227-0
摘要	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 (KrasLSL-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.
学科门类	Genetics ; Cancer Research
URL	查看原文
收录类别	SCOPUS
语种	英语
原始文献类型	Article
Scopus 记录号	2-s2.0-85146101640
来源库	SCOPUS
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/286438
专题	生命科学与技术学院生命科学与技术学院_特聘教授组_季红斌组生命科学与技术学院_特聘教授组_陈洛南组生命科学与技术学院_特聘教授组_李林组
作者单位	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
推荐引用方式 GB/T 7714	Fang, Zhaoyuan,Han, Xiangkun,Chen, Yueqing,et al. Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation[J]. SIGNAL TRANSDUCTION AND TARGETED THERAPY;,2023,8(1).
APA	Fang, Zhaoyuan.,Han, Xiangkun.,Chen, Yueqing.,Tong, Xinyuan.,Xue, Yun.,...&Ji, Hongbin.(2023).Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation.SIGNAL TRANSDUCTION AND TARGETED THERAPY;,8(1).
MLA	Fang, Zhaoyuan,et al."Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation".SIGNAL TRANSDUCTION AND TARGETED THERAPY; 8.1(2023).