Onco-fetal reprogramming of endothelial cells drives immunosuppressive macrophages in Hepatocellular Carcinoma (Sharma et al)

Published: 21-09-2020| Version 1 | DOI: 10.17632/6wmzcskt6k.1
Ankur Sharma


Liver dysfunction is associated with diseases ranging from metabolic disorders to hepatocellular carcinomas (HCC). Here we employed single-cell RNA-sequencing to extensively characterise the cellular landscape of human liver, from development to disease. We analysed ~212,000 cells representing human fetal liver, HCC and mouse liver. Our analysis revealed a remarkable fetal-like reprogramming of the tumor microenvironment (TME). Specifically, the HCC ecosystem displayed features reminiscent of fetal development, including the re-emergence of fetal-associated endothelial cells (PLVAP+/VEGFR2+), and fetal-like (FOLR2+) tumor-associated macrophages (TAMs). In a cross-species comparative analysis, we discovered remarkable similarity of gene expression and regulatory networks between mouse embryonically-seeded, fetal-liver and FOLR2+ tumor macrophages. Spatial transcriptomics further corroborated 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 between the human fetal-liver and HCC. Our results unravel a previously unexplored onco-fetal reprogramming of tumor ecosystem, provides a novel target for therapeutic interventions in HCC and also opens up avenues for identifying similar paradigms in other cancers and disease states.