{"title":"Wnt缺陷和缺氧环境协调人类胰腺导管腺癌的鳞状重塑","authors":"Hiroki Tamagawa, Masayuki Fujii, Kazuhiro Togasaki, Takashi Seino, Shintaro Kawasaki, Ai Takano, Kohta Toshimitsu, Sirirat Takahashi, Yuki Ohta, Mami Matano, Kenta Kawasaki, Yujiro Machida, Shigeki Sekine, Akihito Machinaga, Ken Sasai, Yuzo Kodama, Nobuyuki Kakiuchi, Seishi Ogawa, Tomonori Hirano, Hiroshi Seno, Minoru Kitago, Yuko Kitagawa, Eisuke Iwasaki, Takanori Kanai, Toshiro Sato","doi":"10.1038/s41556-024-01498-5","DOIUrl":null,"url":null,"abstract":"Human pancreatic cancer is characterized by the molecular diversity encompassing native duct-like and squamous cell-like identities, but mechanisms underlying squamous transdifferentiation have remained elusive. To comprehensively capture the molecular diversity of human pancreatic cancer, we here profiled 65 patient-derived pancreatic cancer organoid lines, including six adenosquamous carcinoma lines. H3K27me3-mediated erasure of the ductal lineage specifiers and hijacking of the TP63-driven squamous-cell programme drove squamous-cell commitment, providing survival benefit in a Wnt-deficient environment and hypoxic conditions. Gene engineering of normal pancreatic duct organoids revealed that GATA6 loss and a Wnt-deficient environment, in concert with genetic or hypoxia-mediated inactivation of KDM6A, facilitate squamous reprogramming, which in turn enhances environmental fitness. EZH2 inhibition counterbalanced the epigenetic bias and curbed the growth of adenosquamous cancer organoids. Our results demonstrate how an adversarial microenvironment dictates the molecular and histological evolution of human pancreatic cancer and provide insights into the principles and significance of lineage conversion in human cancer. Tamagawa, Fujii et al. demonstrate that squamous differentiation in human pancreatic cancer can be attributed to TP63-mediated lineage conversion and epigenetic reprogramming that depends upon a hypoxic and Wnt-defective niche.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3000,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Wnt-deficient and hypoxic environment orchestrates squamous reprogramming of human pancreatic ductal adenocarcinoma\",\"authors\":\"Hiroki Tamagawa, Masayuki Fujii, Kazuhiro Togasaki, Takashi Seino, Shintaro Kawasaki, Ai Takano, Kohta Toshimitsu, Sirirat Takahashi, Yuki Ohta, Mami Matano, Kenta Kawasaki, Yujiro Machida, Shigeki Sekine, Akihito Machinaga, Ken Sasai, Yuzo Kodama, Nobuyuki Kakiuchi, Seishi Ogawa, Tomonori Hirano, Hiroshi Seno, Minoru Kitago, Yuko Kitagawa, Eisuke Iwasaki, Takanori Kanai, Toshiro Sato\",\"doi\":\"10.1038/s41556-024-01498-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Human pancreatic cancer is characterized by the molecular diversity encompassing native duct-like and squamous cell-like identities, but mechanisms underlying squamous transdifferentiation have remained elusive. To comprehensively capture the molecular diversity of human pancreatic cancer, we here profiled 65 patient-derived pancreatic cancer organoid lines, including six adenosquamous carcinoma lines. H3K27me3-mediated erasure of the ductal lineage specifiers and hijacking of the TP63-driven squamous-cell programme drove squamous-cell commitment, providing survival benefit in a Wnt-deficient environment and hypoxic conditions. Gene engineering of normal pancreatic duct organoids revealed that GATA6 loss and a Wnt-deficient environment, in concert with genetic or hypoxia-mediated inactivation of KDM6A, facilitate squamous reprogramming, which in turn enhances environmental fitness. EZH2 inhibition counterbalanced the epigenetic bias and curbed the growth of adenosquamous cancer organoids. Our results demonstrate how an adversarial microenvironment dictates the molecular and histological evolution of human pancreatic cancer and provide insights into the principles and significance of lineage conversion in human cancer. Tamagawa, Fujii et al. demonstrate that squamous differentiation in human pancreatic cancer can be attributed to TP63-mediated lineage conversion and epigenetic reprogramming that depends upon a hypoxic and Wnt-defective niche.\",\"PeriodicalId\":18977,\"journal\":{\"name\":\"Nature Cell Biology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":17.3000,\"publicationDate\":\"2024-09-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Cell Biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.nature.com/articles/s41556-024-01498-5\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Cell Biology","FirstCategoryId":"99","ListUrlMain":"https://www.nature.com/articles/s41556-024-01498-5","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Wnt-deficient and hypoxic environment orchestrates squamous reprogramming of human pancreatic ductal adenocarcinoma
Human pancreatic cancer is characterized by the molecular diversity encompassing native duct-like and squamous cell-like identities, but mechanisms underlying squamous transdifferentiation have remained elusive. To comprehensively capture the molecular diversity of human pancreatic cancer, we here profiled 65 patient-derived pancreatic cancer organoid lines, including six adenosquamous carcinoma lines. H3K27me3-mediated erasure of the ductal lineage specifiers and hijacking of the TP63-driven squamous-cell programme drove squamous-cell commitment, providing survival benefit in a Wnt-deficient environment and hypoxic conditions. Gene engineering of normal pancreatic duct organoids revealed that GATA6 loss and a Wnt-deficient environment, in concert with genetic or hypoxia-mediated inactivation of KDM6A, facilitate squamous reprogramming, which in turn enhances environmental fitness. EZH2 inhibition counterbalanced the epigenetic bias and curbed the growth of adenosquamous cancer organoids. Our results demonstrate how an adversarial microenvironment dictates the molecular and histological evolution of human pancreatic cancer and provide insights into the principles and significance of lineage conversion in human cancer. Tamagawa, Fujii et al. demonstrate that squamous differentiation in human pancreatic cancer can be attributed to TP63-mediated lineage conversion and epigenetic reprogramming that depends upon a hypoxic and Wnt-defective niche.
期刊介绍:
Nature Cell Biology, a prestigious journal, upholds a commitment to publishing papers of the highest quality across all areas of cell biology, with a particular focus on elucidating mechanisms underlying fundamental cell biological processes. The journal's broad scope encompasses various areas of interest, including but not limited to:
-Autophagy
-Cancer biology
-Cell adhesion and migration
-Cell cycle and growth
-Cell death
-Chromatin and epigenetics
-Cytoskeletal dynamics
-Developmental biology
-DNA replication and repair
-Mechanisms of human disease
-Mechanobiology
-Membrane traffic and dynamics
-Metabolism
-Nuclear organization and dynamics
-Organelle biology
-Proteolysis and quality control
-RNA biology
-Signal transduction
-Stem cell biology