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

被引：449

作者：

Sharma, Ankur ^{[1
]}

Seow, Justine Jia Wen ^{[1
]}

Dutertre, Charles-Antoine ^{[2
,3
]}

Pai, Rhea ^{[1
]}

Bleriot, Camille ^{[2
]}

Mishra, Archita ^{[2
]}

Wong, Regina Men Men ^{[1
]}

Singh, Gurmit Singh Naranjan ^{[2
]}

Sudhagar, Samydurai ^{[1
]}

Khalilnezhad, Shabnam ^{[2
]}

Erdal, Sergio ^{[2
]}

Teo, Hui Min ^{[1
]}

Khalilnezhad, Ahad ^{[2
]}

Chakarov, Svetoslav ^{[2
]}

Lim, Tony Kiat Hon ^{[4
]}

Fui, Alexander Chung Yaw ^{[5
]}

Chieh, Alfred Kow Wei ^{[6
]}

Chung, Cheow Peng ^{[5
]}

Bonney, Glenn Kunnath ^{[6
]}

Goh, Brian Kim-Poh ^{[5
]}

Chan, Jerry K. Y. ^{[7
,8
,9
]}

Chow, Pierce K. H. ^{[10
,11
]}

Ginhoux, Florent ^{[2
,12
,13
]}

DasGupta, Ramanuj ^{[1
]}

机构：

[1] ASTAR, Genome Inst Singapore, 60 Biopolis St,Genome 02-01, Singapore 138672, Singapore

[2] ASTAR, Singapore Immunol Network SIgN, 8A Biomed Grove,Immunos Bldg,Level 3&4, Singapore 138648, Singapore

[3] Duke NUS Med Sch, Program Emerging Infect Dis, 8 Coll Rd, Singapore 169857, Singapore

[4] Singapore Gen Hosp, Dept Pathol, Singapore 169608, Singapore

[5] Singapore Gen Hosp, Dept Hepatopancreatobiliary & Transplant Surg, Singapore 169608, Singapore

[6] Natl Univ Singapore Hosp, Dept Surg, Div Hepatobiliary & Pancreat Surg, Singapore 119074, Singapore

[7] KK Womens & Childrens Hosp, Dept Reprod Med, Singapore 229899, Singapore

[8] NUS, Dept Obstet & Gynaecol, Yong Loo Lin Sch Med, Expt Fetal Med Grp, Singapore 117597, Singapore

[9] Duke NUS Med Sch, Acad Clin Program Obstet & Gynaecol, Singapore 169857, Singapore

[10] Natl Canc Ctr, Div Surg & Surg Oncol, Singapore 169610, Singapore

[11] Duke NUS Med Sch, Acad Clin Programme Surg, Singapore 169857, Singapore

[12] Shanghai Jiao Tong Univ, Shanghai Inst Immunol, Sch Med, Shanghai 200025, Peoples R China

[13] SingHlth Duke NUS Acad Med Ctr, Translat Immunol Inst, Singapore 169856, Singapore

来源：

CELL | 2020年 / 183卷 / 02期

基金：

英国医学研究理事会;

关键词：

REGENERATION;

D O I：

10.1016/j.cell.2020.08.040

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We employed scRNA sequencing to extensively characterize the cellular landscape of human liver from development to disease. Analysis of similar to 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.

引用

页码：377 / +

页数：39

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