Cell · 2020
Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Sharma Ankur, Seow Justine Jia Wen, Dutertre Charles-Antoine, Pai Rhea, Blériot Camille, Mishra Archita, Wong Regina Men Men, Singh Gurmit Singh Naranjan, Sudhagar Samydurai, Khalilnezhad Shabnam, Erdal Sergio, Teo Hui Min, Khalilnezhad Ahad, Chakarov Svetoslav, Lim Tony Kiat Hon, Fui Alexander Chung Yaw, Chieh Alfred Kow Wei, Chung Cheow Peng, Bonney Glenn Kunnath, Goh Brian Kim-Poh, Chan Jerry K Y, Chow Pierce K H, Ginhoux Florent, DasGupta Ramanuj
Аннотация
We employed scRNA sequencing to extensively characterize the cellular landscape of human liver from development to disease. Analysis of ∼212,000 cells representing human fetal, hepatocellular carcinoma (HCC), and mouse liver revealed remarkable fetal-like reprogramming of the tumor microenvironment. Specifically, the HCC ecosystem displayed features reminiscent of fetal development, including re-emergence of fetal-associated endothelial cells (PLVAP/VEGFR2) and fetal-like (FOLR2) tumor-associated macrophages. In a cross-species comparative analysis, we discovered remarkable similarity between mouse embryonic, fetal-liver, and tumor macrophages. Spatial transcriptomics further revealed a shared onco-fetal ecosystem between fetal liver and HCC. Furthermore, gene regulatory analysis, spatial transcriptomics, and in vitro functional assays implicated VEGF and NOTCH signaling in maintaining onco-fetal ecosystem. Taken together, we report a shared immunosuppressive onco-fetal ecosystem in fetal liver and HCC. Our results unravel a previously unexplored onco-fetal reprogramming of the tumor ecosystem, provide novel targets for therapeutic interventions in HCC, and open avenues for identifying similar paradigms in other cancers and disease.
Предметные рубрики MeSH
AdultAnimalsCarcinoma, HepatocellularCell LineDisease Models, AnimalEndothelial CellsFemaleFolate Receptor 2Gene Expression ProfilingHumansLiverLiver NeoplasmsMacrophagesMaleMembrane ProteinsMiceReceptors, NotchSignal TransductionTranscriptomeTumor MicroenvironmentVascular Endothelial Growth Factor Receptor-2