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
Mitogen-activated protein(MAP)kinases comprise a family of protein-serine/threonine kinases,which are highly conserved in protein structures from unicellular eukaryotic organisms to multicellular organisms,including m...Mitogen-activated protein(MAP)kinases comprise a family of protein-serine/threonine kinases,which are highly conserved in protein structures from unicellular eukaryotic organisms to multicellular organisms,including mammals.These kinases,including ERKs,JNKs and p38s,are regulated by a phosphorelay cascade,with a prototype of three protein kinases that sequentially phosphorylate one another.MAPKs transduce extracellular signals into a variety of cellular processes,such as cell proliferation,survival,death,and differentiation.Consistent with their essential cellular functions,MAPKs have been shown to play critical roles in embryonic development,adult tissue homeostasis and various pathologies.In this review,we discuss recent findings that reveal the profound impact of these pathways on chronic inflammation and,particularly,inflammation-associated cancer development.展开更多
Although IL-12 plays a critical role in priming Th1 and cytotoxic T lymphocyte(CTL) responses, Toll-like receptor(TLR) signaling only induces low amounts of IL-12 in dendritic cells and macrophages, implying the exist...Although IL-12 plays a critical role in priming Th1 and cytotoxic T lymphocyte(CTL) responses, Toll-like receptor(TLR) signaling only induces low amounts of IL-12 in dendritic cells and macrophages, implying the existence of stringent regulatory mechanisms. In this study, we sought to uncover the mechanisms underlying TLR-induced IL-12 expression and the Th1 response. By systemic screening, we identified a number of protein kinases involved in the regulation of TLRinduced IL-12 expression. In particular, PI3 K, ERK, and m TOR play critical roles in the TLR-induced Th1 response by regulating IL-12 and IL-10 production in innate immune cells. Moreover, we identified c-fos as a key molecule that mediates m TOR-regulated IL-12 and IL-10 expression in TLR signaling. Mechanistically, m TOR plays a crucial role in c-fos expression, thereby modulating NFκB binding to promoters of IL-12 and IL-10. By controlling the expression of a special innate gene program, m TOR can specifically regulate the TLR-induced T cell response in vivo. Furthermore, blockade of m TOR by rapamycin efficiently boosted TLR-induced antigen-specific T and B cell responses to HBV and HCV vaccines. Taken together, these results reveal a novel mechanism through which m TOR regulates TLR-induced IL-12 and IL-10 production, contributing new insights for strategies to improve vaccine efficacy.展开更多
Understanding the development,regeneration,and disorders of the liver is the major goal in liver biology.Current mechanistic knowledge of human livers has been largely derived from mouse models and cell lines,which fa...Understanding the development,regeneration,and disorders of the liver is the major goal in liver biology.Current mechanistic knowledge of human livers has been largely derived from mouse models and cell lines,which fall short in recapitulating the features of human liver cells or the structures and functions of human livers.Organoids as an in vitro system hold the promise to generate organ-like tissues in a dish.Recent advances in human liver organoids also facilitate the understanding of the biology and diseases in this complex organ.Here we review the progress in human liver organoids,mainly focusing on the methods to generate liver organoids,their applications,and possible future directions.展开更多
Stem cells are undifferentiated cells capable of self-renewal and differentiation,giving rise to specialized functional cells.Stem cells are of pivotal importance for organ and tissue development,homeostasis,and injur...Stem cells are undifferentiated cells capable of self-renewal and differentiation,giving rise to specialized functional cells.Stem cells are of pivotal importance for organ and tissue development,homeostasis,and injury and disease repair.Tissue-specific stem cells are a rare population residing in specific tissues and present powerful potential for regeneration when required.They are usually named based on the resident tissue,such as hematopoietic stem cells and germline stem cells.This review discusses the recent advances in stem cells of various tissues,including neural stem cells,muscle stem cells,liver progenitors,pancreatic islet stem/progenitor cells,intestinal stem cells,and prostate stem cells,and the future perspectives for tissue stem cell research.展开更多
Transcriptional regulators(TRs)participate in essential processes in cancer pathogenesis and are critical therapeutic targets.Identification of drug response-related TRs from cell line-based compound screening data is...Transcriptional regulators(TRs)participate in essential processes in cancer pathogenesis and are critical therapeutic targets.Identification of drug response-related TRs from cell line-based compound screening data is often challenging due to low m RNA abundance of TRs,protein modifications,and other confounders(CFs).In this study,we developed a regression-based pharmacogenomic and Ch IP-seq data integration method(Re Phine)to infer the impact of TRs on drug response through integrative analyses of pharmacogenomic and Ch IP-seq data.Re Phine was evaluated in simulation and pharmacogenomic data and was applied to pan-cancer datasets with the goal of biological discovery.In simulation data with added noises or CFs and in pharmacogenomic data,Re Phine demonstrated an improved performance in comparison with three commonly used methods(including Pearson correlation analysis,logistic regression model,and gene set enrichment analysis).Utilizing Re Phine and Cancer Cell Line Encyclopedia data,we observed that Re Phinederived TR signatures could effectively cluster drugs with different mechanisms of action.Re Phine predicted that loss-offunction of EZH2/PRC2 reduces cancer cell sensitivity toward the BRAF inhibitor PLX4720.Experimental validation confirmed that pharmacological EZH2 inhibition increases the resistance of cancer cells to PLX4720 treatment.Our results support that Re Phine is a useful tool for inferring drug response-related TRs and for potential therapeutic applications.The source code for Re Phine is freely available at https://github.com/coexps/Re Phine.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.
基金The work in L.H.laboratory is supported by Shanghai Pujiang Program 09PJ1411200the Knowledge Innovation Program of Shanghai Institutes for Biological Sciences 2009KIP101+1 种基金the Knowledge Innovation Program of the Chinese Academy of Sciences KSCX2-YW-R-241work in J.H.laboratory is supported by Chinese 973 program 2009CB522200,Chinese NSF grant 30830092,Chinese-Switzerland collaboration grant 2009DFA32760.
文摘Mitogen-activated protein(MAP)kinases comprise a family of protein-serine/threonine kinases,which are highly conserved in protein structures from unicellular eukaryotic organisms to multicellular organisms,including mammals.These kinases,including ERKs,JNKs and p38s,are regulated by a phosphorelay cascade,with a prototype of three protein kinases that sequentially phosphorylate one another.MAPKs transduce extracellular signals into a variety of cellular processes,such as cell proliferation,survival,death,and differentiation.Consistent with their essential cellular functions,MAPKs have been shown to play critical roles in embryonic development,adult tissue homeostasis and various pathologies.In this review,we discuss recent findings that reveal the profound impact of these pathways on chronic inflammation and,particularly,inflammation-associated cancer development.
基金support by National Natural Science Foundation of China grants 31070779 and 31170862 (to H.X.), 31100623 (to A.Z.) and 31270917 (to M.D.)National Key laboratory of Virology grant (2014IOV006)+3 种基金H.X. is supported by Chinese Academy of Sciences "100-talent" programNational program for returned oversea talentsthe CAS/SAFEA International Partnership Program for Creative Research TeamsShanghai Pasteur foundation
文摘Although IL-12 plays a critical role in priming Th1 and cytotoxic T lymphocyte(CTL) responses, Toll-like receptor(TLR) signaling only induces low amounts of IL-12 in dendritic cells and macrophages, implying the existence of stringent regulatory mechanisms. In this study, we sought to uncover the mechanisms underlying TLR-induced IL-12 expression and the Th1 response. By systemic screening, we identified a number of protein kinases involved in the regulation of TLRinduced IL-12 expression. In particular, PI3 K, ERK, and m TOR play critical roles in the TLR-induced Th1 response by regulating IL-12 and IL-10 production in innate immune cells. Moreover, we identified c-fos as a key molecule that mediates m TOR-regulated IL-12 and IL-10 expression in TLR signaling. Mechanistically, m TOR plays a crucial role in c-fos expression, thereby modulating NFκB binding to promoters of IL-12 and IL-10. By controlling the expression of a special innate gene program, m TOR can specifically regulate the TLR-induced T cell response in vivo. Furthermore, blockade of m TOR by rapamycin efficiently boosted TLR-induced antigen-specific T and B cell responses to HBV and HCV vaccines. Taken together, these results reveal a novel mechanism through which m TOR regulates TLR-induced IL-12 and IL-10 production, contributing new insights for strategies to improve vaccine efficacy.
基金This study is supported by the Chinese Academy of Sciences(XDA16020201 and XDA12050104)the National Science and Technology Major Project*Key New Drug Creation and Manufacturing Program,(2018ZX09711002-009).
文摘Understanding the development,regeneration,and disorders of the liver is the major goal in liver biology.Current mechanistic knowledge of human livers has been largely derived from mouse models and cell lines,which fall short in recapitulating the features of human liver cells or the structures and functions of human livers.Organoids as an in vitro system hold the promise to generate organ-like tissues in a dish.Recent advances in human liver organoids also facilitate the understanding of the biology and diseases in this complex organ.Here we review the progress in human liver organoids,mainly focusing on the methods to generate liver organoids,their applications,and possible future directions.
基金supported by grants from the National Natural Science Foundation of China(31988101 and 31730056 to YGC32125013 and 81772723 to DG+15 种基金32170804 to PH31930030 to LH91732301,31671072,31771140,81891001,91432111,81527901,31400977,31625013 to XW31625020,31830056,31861163006 to YAZ)the Ministry of Science and Technology of China(2017YFA0103601 to YGC2020YFA0509000,2017YFA0505500 to DG2017YFA0102700 to PH2019YFA0802001,2019YFA0801503 to LH2017YFA0102601,2019YFA0110100 to XW2020YFA0509002,2019YFA0802002 to YAZ)the Strategic Priority Research Program of the Chinese Academy of Science(XDA16020400 to PHXDA16020200 to YAZ)the Shanghai Science and Technology Commission(21XD1424200,21ZR1470100 to DG)the Basic Frontier Science Research Program of Chinese Academy of Sciences(ZDBS-LY-SM015 to DG)Space Medical Experiment Project of China Manned Space Program(HYZHXM01017 to PH)the Grants of Beijing Brain Initiative of Beijing Municipal Science&Technology Commission(Z181100001518004 to XW)。
文摘Stem cells are undifferentiated cells capable of self-renewal and differentiation,giving rise to specialized functional cells.Stem cells are of pivotal importance for organ and tissue development,homeostasis,and injury and disease repair.Tissue-specific stem cells are a rare population residing in specific tissues and present powerful potential for regeneration when required.They are usually named based on the resident tissue,such as hematopoietic stem cells and germline stem cells.This review discusses the recent advances in stem cells of various tissues,including neural stem cells,muscle stem cells,liver progenitors,pancreatic islet stem/progenitor cells,intestinal stem cells,and prostate stem cells,and the future perspectives for tissue stem cell research.
基金supported by the National Key R&D Program of China(2018YFC0910500)the Neil Shen’s SJTU Medical Research Fund+6 种基金the SJTU-Yale Collaborative Research Seed Fundthe National Natural Science Foundation of China(Grant Nos.31370751 and 31728012)the Shanghai Municipal Commission of Health and Family Planning(Grant No.20144Y0179)the Science and Technology Commission of Shanghai Municipality(STCSM)(Grant No.17DZ 22512000)the Shanghai Municipal Science and Technology Major Project(Grant No.2018SHZDZX01)the Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence(LCNBI)ZJLab。
文摘Transcriptional regulators(TRs)participate in essential processes in cancer pathogenesis and are critical therapeutic targets.Identification of drug response-related TRs from cell line-based compound screening data is often challenging due to low m RNA abundance of TRs,protein modifications,and other confounders(CFs).In this study,we developed a regression-based pharmacogenomic and Ch IP-seq data integration method(Re Phine)to infer the impact of TRs on drug response through integrative analyses of pharmacogenomic and Ch IP-seq data.Re Phine was evaluated in simulation and pharmacogenomic data and was applied to pan-cancer datasets with the goal of biological discovery.In simulation data with added noises or CFs and in pharmacogenomic data,Re Phine demonstrated an improved performance in comparison with three commonly used methods(including Pearson correlation analysis,logistic regression model,and gene set enrichment analysis).Utilizing Re Phine and Cancer Cell Line Encyclopedia data,we observed that Re Phinederived TR signatures could effectively cluster drugs with different mechanisms of action.Re Phine predicted that loss-offunction of EZH2/PRC2 reduces cancer cell sensitivity toward the BRAF inhibitor PLX4720.Experimental validation confirmed that pharmacological EZH2 inhibition increases the resistance of cancer cells to PLX4720 treatment.Our results support that Re Phine is a useful tool for inferring drug response-related TRs and for potential therapeutic applications.The source code for Re Phine is freely available at https://github.com/coexps/Re Phine.