Onco-fetal reprogramming of endothelial cells drives immunosuppressive macrophages in Hepatocellular Carcinoma (Nanostring)
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Summary:
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.Overall design:
Analysis of hepatocellular carcinoma (HCC) and human fetal liver samples ,Tissue slides from 3 HCC patients (adjacent normal & tumor section for each) and 3 human fetal liver samples were used for this experiment. 12 regions of interests were selected for each of the 9 samples so a total of 108 regions of interests were analysed. The samples were stained with 96 targets (immune, stromal, epithelial and onco-fetal markers).Technology:
GeoMx DSP
Platform:
Multiplex spatial transcriptomics assay
Species:
Homo sapiens(hg38)
Tissues:
Liver
Organ parts:
Liver, Fetal liver
Citation:
Sharma, Ankur et al. “Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma.” Cell vol. 183,2 (2020): 377-394.e21. doi:10.1016/j.cell.2020.08.040Submission date: 2020-08-21Update date: 2020-09-27
Contributors
Sharma A; Seow JW; Dutertre C; Pai R; Blériot C; Mishra A; Wong RM; Singh GS; Sudhagar S; Khalilnezhad S; Erdal S; Teo HM; Khalilnezhad A; Chakarov S; Lim TK; Chung AY; Kow AW; Cheow PC; Bonney GK; Goh BK; Chan JK; Chow PK; Ginhoux F; DasGupta R
Contact: sharmaa@gis.a-star.edu.sg