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Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma (14 HCC and 4 fetal liver tissues)
Ankur Sharma, Justine Jia Wen Seow, Charles-Antoine Dutertre, Rhea Pai, Camille Blériot, Archita Mishra, Regina Men Men Wong, Gurmit Singh Naranjan Singh, Samydurai Sudhagar, Shabnam Khalilnezhad, Sergio Erdal, Hui Min Teo, Ahad Khalilnezhad, Svetoslav Chakarov, Tony Kiat Hon Lim, Alexander Chung Yaw Fui, Alfred Kow Wei Chieh, Cheow Peng Chung, Glenn Kunnath Bonney, Brian Goh Kim Poh, Jerry K.Y. Chan, Pierce K.H. Chow, Florent Ginhoux, Ramanuj DasGupta
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.