Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma

• Published in: Cell 2020-10, Vol.183 (2), p.377-394.e21
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: endothelial cells; FOLR2; HCC; Hepatocellular carcinoma; NOTCH; onco-fetal reprogramming; PLVAP; scRNA-seq; TAMs; tumor associated macrophages; tumor microenvironment
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2020.08.040

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. [Display omitted] •Identification of fetal-associated endothelial cells and macrophages in HCC•Embryonic-like reprogramming in a subset of FOLR2+ TAM1s•Conserved GRN in mouse embryonically seeded, human fetal-liver, and TAM1 macrophages•Shared onco-fetal ecosystem between human fetal liver and HCC A single-cell atlas of human liver from development to disease suggests a shared onco-fetal ecosystem driving immunosuppression in fetal liver and hepatocellular carcinoma.