Liver Cancer Endothelial and Myeloid Cells Exhibit Fetal Reprogramming

Reactivation of early developmental programs in tumor cells has been documented, but much remains unknown about the implications of fetal reprogramming of other cells in the tumor microenvironment. To investigate this, Sharma and colleagues performed a detailed single-cell analysis of healthy human fetal liver, healthy human adult liver, human hepatocellular carcinoma (HCC) plus adjacent healthy tissue from multiple hepatitis B⁺ and hepatitis B⁻ patients, and liver from mouse models. Single-cell RNA sequencing revealed that differences between tumor tissue and healthy surrounding tissue were especially marked in endothelial cells and macrophages. Notably, a subset of tumor endothelial cells expressed PLVAP, encoding an endothelial cell–specific protein with established importance in liver development and HCC, and many of the tumor-associated macrophages expressed FOLR2, encoding a folate receptor that is also highly expressed in placental tissue. Importantly, PLVAP⁺ endothelial cells and FOLR2⁺ macrophages were also enriched in human fetal liver. A large subset of PLVAP⁺ tumor-associated endothelial cells expressed VEGFR2, encoding the receptor for the angiogenesis-promoting growth factor VEGF. The secretion of VEGF by hepatocytes is known to regulate PLVAP expression, suggesting a role for VEGF signaling in fetal-like reprogramming of HCC-associated endothelial cells. An analysis of cell–cell interactions in the tumor microenvironment revealed close association between a fetal-like subgroup of FOLR2⁺ tumor-associated macrophages and immunosuppressive regulatory T cells, indicating that these macrophages may contribute to immunosuppression in the tumor microenvironment; additionally, both cell types were spatially colocalized with PLVAP⁺ endothelial cells. Gene-regulatory network analyses revealed shared regulons, further strengthening the connection between fetal-like FOLR2⁺ tumor-associated macrophages and fetal liver macrophages. One such regulon included HES1, encoding a transcription factor that acts as a downstream effector in the NOTCH pathway, and further experiments suggested that fetal-like PLVAP⁺ endothelial cells may be the source of NOTCH pathway–activating ligand. Collectively, these results are indicative of fetal-like reprogramming in subsets of liver tumor–associated endothelial cells and macrophages.

Sharma A, Seow JJW, Dutertre CA, Pai R, Blériot C, Mishra A, et al. Onco-fetal reprogramming of endothelial cells drives immunosuppressive macrophages in hepatocellular carcinoma. Cell 2020;183:377–94.E21.

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