TY - JOUR
T1 - Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma
AU - Sharma, Ankur
AU - Seow, Justine Jia Wen
AU - Dutertre, Charles Antoine
AU - Pai, Rhea
AU - Blériot, Camille
AU - Mishra, Archita
AU - Wong, Regina Men Men
AU - Singh, Gurmit Singh Naranjan
AU - Sudhagar, Samydurai
AU - Khalilnezhad, Shabnam
AU - Erdal, Sergio
AU - Teo, Hui Min
AU - Khalilnezhad, Ahad
AU - Chakarov, Svetoslav
AU - Lim, Tony Kiat Hon
AU - Fui, Alexander Chung Yaw
AU - Chieh, Alfred Kow Wei
AU - Chung, Cheow Peng
AU - Bonney, Glenn Kunnath
AU - Goh, Brian Kim Poh
AU - Chan, Jerry K.Y.
AU - Chow, Pierce K.H.
AU - Ginhoux, Florent
AU - DasGupta, Ramanuj
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/10/15
Y1 - 2020/10/15
N2 - 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.
AB - 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.
KW - FOLR2
KW - HCC
KW - Hepatocellular carcinoma
KW - NOTCH
KW - PLVAP
KW - TAMs
KW - endothelial cells
KW - onco-fetal reprogramming
KW - scRNA-seq
KW - tumor associated macrophages
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85091614152&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2020.08.040
DO - 10.1016/j.cell.2020.08.040
M3 - Article
C2 - 32976798
AN - SCOPUS:85091614152
SN - 0092-8674
VL - 183
SP - 377-394.e21
JO - Cell
JF - Cell
IS - 2
ER -