Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma
Open accessAbstract
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.
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Reprogramming of the liver microenvironment is a key feature of hepatocarcinogenesis, encompassing metabolic alterations of hepatocyte and immune cells, re-emergence of fetal-associated endothelial cells and altered inflammatory milieu.
“Reprogramming of liver microenvironment is a key feature of hepatocarcinogenesis, which encompasses but not limited to metabolic alterations of hepatocyte and immune cells, re-emergence of fetal-associated endothelial cells and altered inflammatory milieu [10, 46, 65, 66].”
From Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC (2025) · cites this paper as [66]
Cites
UMAP: Uniform Manifold Approximation and Projection
McInnes, L., Healy, J., Saul, N., & Großberger, L. (2018) · Journal of Open Source Software · doi:10.21105/joss.00861 · Cited by 9,826 · see citing works
Scenic: single-cell regulatory network inference and clustering.
Aibar, S., González-Blas, C. B., Moerman, T., Huynh-Thu, V. A., Imrichova, H., Hulselmans, G., Rambow, F., Marine, J.-C., Geurts, P., Aerts, J., et al. (2017) · Nature Methods · doi:10.1038/nmeth.4463 · Cited by 6,520 · see citing works
Clonal heterogeneity and tumor evolution: past, present, and the future
McGranahan, N., & Swanton, C. (2017) · Cell · doi:10.1016/j.cell.2017.01.018 · Cited by 2,840 · see citing works
Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma
Zhang, Q., He, Y., Luo, N., Patel, S. J., Han, Y., Gao, R., Modak, M., Carotta, S., Haslinger, C., Kind, D., et al. (2019) · Cell · doi:10.1016/j.cell.2019.10.003 · Cited by 1,624 · see citing works
Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner
Jaitin, D. A., Adlung, L., Thaiss, C. A., Weiner, A., Li, B., Descamps, H., Lundgren, P., Bleriot, C., Liu, Z., Deczkowska, A., et al. (2019) · Cell · doi:10.1016/j.cell.2019.05.054 · Cited by 1,377 · see citing works
Self-citationChakarov, S., Lim, H. Y., Tan, L., Lim, S. Y., See, P., Lum, J., Zhang, X.-M., Foo, S., Nakamizo, S., Duan, K., et al. (2019) · Science · doi:10.1126/science.aau0964 · Cited by 1,114 · see citing works
Self-citationBonnardel, J., T’Jonck, W., Gaublomme, D., Browaeys, R., Scott, C. L., Martens, L., Vanneste, B., De Prijck, S., Nedospasov, S. A., Kremer, A., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.08.017 · Cited by 631 · see citing works
Sakai, M., Troutman, T. D., Seidman, J. S., Ouyang, Z., Spann, N. J., Abe, Y., Ego, K. M., Bruni, C. M., Deng, Z., Schlachetzki, J. C. M., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.09.002 · Cited by 418 · see citing works
Rantakari, P., Auvinen, K., Jäppinen, N., Kapraali, M., Valtonen, J., Karikoski, M., Gerke, H., Iftakhar-E-Khuda, I., Keuschnigg, J., Umemoto, E., et al. (2015) · Nature Immunology · doi:10.1038/ni.3101 · Cited by 203 · see citing works
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Cited by
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A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells
Cheng, S., Li, Z., Gao, R., Xing, B., Gao, Y., Yang, Y., Qin, S., Zhang, L., Ouyang, H., Du, P., et al. (2021) · Cell · doi:10.1016/j.cell.2021.01.010 · Cited by 1,601 · see citing works
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches
Guilliams, M., Bonnardel, J., Haest, B., Vanderborght, B., Wagner, C., Remmerie, A., Bujko, A., Martens, L., Thoné, T., Browaeys, R., et al. (2022) · Cell · doi:10.1016/j.cell.2021.12.018 · Cited by 985 · see citing works
Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease
Mulder, K., Patel, A. A., Kong, W. T., Piot, C., Halitzki, E., Dunsmore, G., Khalilnezhad, S., Irac, S. E., Dubuisson, A., Chevrier, M., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.07.007 · Cited by 678 · see citing works
Self-citationZhu, A. X., Abbas, A. R., de Galarreta, M. R., Guan, Y., Lu, S., Koeppen, H., Zhang, W., Hsu, C.-H., He, A. R., Ryoo, B.-Y., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-01868-2 · Cited by 652 · see citing works
Macrophages in health and disease
Park, M. D., Silvin, A., Ginhoux, F., & Merad, M. (2022) · Cell · doi:10.1016/j.cell.2022.10.007 · Cited by 644 · see citing works
Self-citationBarkley, D., Moncada, R., Pour, M., Liberman, D. A., Dryg, I., Werba, G., Wang, W., Baron, M., Rao, A., Xia, B., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01141-9 · Cited by 532 · see citing works
Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)
Cossarizza, A., Chang, H., Radbruch, A., Abrignani, S., Addo, R., Akdis, M., Andrä, I., Andreata, F., Annunziato, F., Arranz, E., et al. (2021) · European Journal of Immunology · doi:10.1002/eji.202170126 · Cited by 531 · see citing works
Self-citationLiver macrophages in health and disease
Guilliams, M., & Scott, C. L. (2022) · Immunity · doi:10.1016/j.immuni.2022.08.002 · Cited by 395 · see citing works
Colonna, M. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00837-1 · Cited by 394 · see citing works
Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation
Fabre, T., Barron, A. M. S., Christensen, S. M., Asano, S., Bound, K., Lech, M. P., Wadsworth, M. H., Chen, X., Wang, C., Wang, J., et al. (2023) · Science Immunology · doi:10.1126/sciimmunol.add8945 · Cited by 355 · see citing works
Andrews, T. S., Atif, J., Liu, J. C., Perciani, C. T., Ma, X., Thoeni, C., Slyper, M., Eraslan, G., Segerstolpe, A., Manuel, J., et al. (2022) · Hepatology Communications · doi:10.1002/hep4.1854 · Cited by 307 · see citing works
A subset of Kupffer cells regulates metabolism through the expression of CD36
Blériot, C., Barreby, E., Dunsmore, G., Ballaire, R., Chakarov, S., Ficht, X., De Simone, G., Andreata, F., Fumagalli, V., Guo, W., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.08.006 · Cited by 236 · see citing works
Self-citationThe spatiotemporal program of zonal liver regeneration following acute injury
Ben-Moshe, S., Veg, T., Manco, R., Dan, S., Papinutti, D., Lifshitz, A., Kolodziejczyk, A. A., Bahar Halpern, K., Elinav, E., & Itzkovitz, S. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.04.008 · Cited by 224 · see citing works
Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution
Watson, B. R., Paul, B., Rahman, R. U., Amir-Zilberstein, L., Segerstolpe, Å., Epstein, E. T., Murphy, S., Geistlinger, L., Lee, T., Shih, A., et al. (2025) · Nature Communications · doi:10.1038/s41467-024-55325-4 · Cited by 123 · see citing works
Temporal analyses of postnatal liver development and maturation by single-cell transcriptomics
Liang, Y., Kaneko, K., Xin, B., Lee, J., Sun, X., Zhang, K., & Feng, G.-S. (2022) · Developmental Cell · doi:10.1016/j.devcel.2022.01.004 · Cited by 116 · see citing works
Inverso, D., Shi, J., Lee, K. H., Jakab, M., Ben-Moshe, S., Kulkarni, S. R., Schneider, M., Wang, G., Komeili, M., Vélez, P. A., et al. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.05.001 · Cited by 114 · see citing works
Neuregulin 4 suppresses NASH-HCC development by restraining tumor-prone liver microenvironment
Zhang, P., Chen, Z., Kuang, H., Liu, T., Zhu, J., Zhou, L., Wang, Q., Xiong, X., Meng, Z., Qiu, X., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.07.010 · Cited by 105 · see citing works
Heterogeneity and Function of Kupffer Cells in Liver Injury
Li, W., Chang, N., & Li, L. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.940867 · Cited by 102 · see citing works
Zhou, L., Wang, M., Guo, H., Hou, J., Zhang, Y., Li, M., Wu, X., Chen, X., & Wang, L. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.848367 · Cited by 85 · see citing works
Spatial transcriptomics identifies enriched gene expression and cell types in human liver fibrosis
Chung, B. K., Øgaard, J., Reims, H. M., Karlsen, T. H., & Melum, E. (2022) · Hepatology Communications · doi:10.1002/hep4.2001 · Cited by 85 · see citing works
CXCL12+ tumor-associated endothelial cells promote immune resistance in hepatocellular carcinoma
Lu, Y., Liu, Y., Zuo, X., Li, G., Wang, J., Liu, J., Wang, X., Wang, S., Zhang, W., Zhang, K., et al. (2025) · Journal of Hepatology · doi:10.1016/j.jhep.2024.09.044 · Cited by 82 · see citing works
Suphavilai, C., Chia, S., Sharma, A., Tu, L., Da Silva, R. P., Mongia, A., DasGupta, R., & Nagarajan, N. (2021) · Genome Medicine · doi:10.1186/s13073-021-01000-y · Cited by 58 · see citing works
Self-citationFetal liver development and implications for liver disease pathogenesis
Lotto, J., Stephan, T. L., & Hoodless, P. A. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00775-2 · Cited by 47 · see citing works
Shen, P., Jia, Y., Zhou, W., Zheng, W., Wu, Y., Qu, S., Du, S., Wang, S., Shi, H., Sun, J., et al. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.04.010 · Cited by 42 · see citing works
Huang, Y., Xie, Y., Zhang, Y., Liu, Z., Jiang, W., Ye, Y., Tang, J., Li, Z., Yin, Z., & Lin, X.-J. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02370-2 · Cited by 41 · see citing works
Wang, Y., Guan, Y., Feng, D., Maccioni, L., Parra, M. A., Peiffer, B., Mackowiak, B., Kuwabara, T., Mori, K., Mukoyama, M., et al. (2025) · Cellular & Molecular Immunology · doi:10.1038/s41423-025-01343-1 · Cited by 23 · see citing works
Zhang, S., Xu, H., Li, M., Yuan, G., Nie, J., Zhang, Q., Shi, J., Liu, D., Meng, H., Dong, W., et al. (2026) · Journal of Hepatology · doi:10.1016/j.jhep.2025.10.026 · Cited by 21 · see citing works
Determinants, mechanisms, and functional outcomes of myeloid cell diversity in cancer
Caronni, N., Montaldo, E., Mezzanzanica, L., Cilenti, F., Genua, M., & Ostuni, R. (2021) · Immunological Reviews · doi:10.1111/imr.12944 · Cited by 6 · see citing works
- Authors
- Sharma, A., Seow, J. J. W., Dutertre, C.-A., Pai, R., Blériot, C., Mishra, A., Wong, R. M. M., Singh, G. S. N., Sudhagar, S., Khalilnezhad, S., Erdal, S., Teo, H. M., Khalilnezhad, A., Chakarov, S., Lim, T. K. H., Fui, A. C. Y., Chieh, A. K. W., Chung, C. P., Bonney, G. K., Goh, B. K.-P., Chan, J. K. Y., Chow, P. K. H., Ginhoux, F., & DasGupta, R.
- Affiliations
- Agency for Science, Technology and Research (SG)
- Singapore General Hospital (SG)
- National University Hospital (SG)
- National University of Singapore (SG)
- SingHealth (SG)
- Corresponding author
- Sharma, Ankur
- Chow, Pierce K.H.
- Ginhoux, Florent
- DasGupta, Ramanuj
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-10
- Volume
- 183
- Issue
- 2
- Pages
- 377-394.e21
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W3087952073
- Cited by
- 677
- References
- 9
- Citations by year
- 2026: 107 · 2025: 120 · 2024: 167 · 2023: 113 · 2022: 107 · 2021: 55 · 2020: 8
- FWCI
- 24.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Funders
- Biomedical Research Council
- National Medical Research Council
- Human Frontier Science Program
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- hepatocellular carcinoma, tumor microenvironment, tumor-associated macrophages, immunosuppression, endothelial cells, VEGFR2, PLVAP, folate receptor beta, VEGF signaling, Notch signaling, fetal liver development, cross-species comparison, spatial transcriptomics
- MeSH terms
- Adult, Animals, Cell Line, Disease Models, Animal, Female, Carcinoma, Hepatocellular, Humans, Liver, Liver Neoplasms, Macrophages, Male, Membrane Proteins, Signal Transduction, Gene Expression Profiling, Vascular Endothelial Growth Factor Receptor-2, Endothelial Cells, Mice, Receptors, Notch, Folate Receptor 2, Tumor Microenvironment, Transcriptome
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