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...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.展开更多
基金We thank Drs.Tyler Jacks,Ronald A.DePinho,Kwok-kin Wong,and Lijian Hui for the generous gift of various mouse strains.We also thank Ruiqi Wang,Rui Liu,Pei Chen,Chao Zheng,and Jifan Shi for helpful discussion.This work was supported by the National Basic Research Program of China(Nos.2017YFA0505500 to H.J.and L.C.,2020YFA0803300 to H.J.)the National Natural Science Foundation of China(Nos.91731314,82030083,31621003,81872312,82011540007 to H.J.,12131020,31930022,12026608 to L.C.,82273093 to Z.F.,81871875,82173340 to L.H.,81802279 to H.H.,81902326 to X.W.,81402371 to Y.J.)+7 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(Nos.XDB19020201 to H.J.,XDB38040400 to L.C.)Basic Frontier Scientific Research Program of Chinese Academy of Science(No.ZDBS-LY-SM006 to H.J.)International Cooperation Project of Chinese Academy of Sciences(No.153D31KYSB20190035 to H.J.)the Science and Technology Commission of Shanghai Municipality(No.21ZR1470300 to L.H.)the Youth Innovation Promotion Association CAS(No.Y919S31371 to X.W.)Special Fund for Science and Technology Innovation Strategy of Guangdong Province(Nos.2021B0909050004,2021B0909060002 to L.C.)Major Key Project of PCL(No.PCL2021A12 to L.C.)JST Moonshot R&D Project(No.JPMJMS2021 to L.C.).
文摘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.
