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Article: A hepatocyte differentiation model reveals two subtypes of liver cancer with different oncofetal properties and therapeutic targets

TitleA hepatocyte differentiation model reveals two subtypes of liver cancer with different oncofetal properties and therapeutic targets
Authors
Keywordshepatocyte differentiation
oncofetal properties
liver development
oncogenic driver
cancer
Issue Date2020
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings of the National Academy of Sciences, 2020, v. 117 n. 11, p. 6103-6113 How to Cite?
AbstractClinical observation of the association between cancer aggressiveness and embryonic development stage implies the importance of developmental signals in cancer initiation and therapeutic resistance. However, the dynamic gene expression during organogenesis and the master oncofetal drivers are still unclear, which impeded the efficient elimination of poor prognostic tumors, including human hepatocellular carcinoma (HCC). In this study, human embryonic stem cells were induced to differentiate into adult hepatocytes along hepatic lineages to mimic liver development in vitro. Combining transcriptomic data from liver cancer patients with the hepatocyte differentiation model, the active genes derived from different hepatic developmental stages and the tumor tissues were selected. Bioinformatic analysis followed by experimental assays was used to validate the tumor subtype-specific oncofetal signatures and potential therapeutic values. Hierarchical clustering analysis revealed the existence of two subtypes of liver cancer with different oncofetal properties. The gene signatures and their clinical significance were further validated in an independent clinical cohort and The Cancer Genome Atlas database. Upstream activator analysis and functional screening further identified E2F1 and SMAD3 as master transcriptional regulators. Small-molecule inhibitors specifically targeting the oncofetal drivers extensively down-regulated subtype-specific developmental signaling and inhibited tumorigenicity. Liver cancer cells and primary HCC tumors with different oncofetal properties also showed selective vulnerability to their specific inhibitors. Further precise targeting of the tumor initiating steps and driving events according to subtype-specific biomarkers might eliminate tumor progression and provide novel therapeutic strategy.
Descriptioneid_2-s2.0-85081702329
Persistent Identifierhttp://hdl.handle.net/10722/284782
ISSN
2019 Impact Factor: 9.412
2015 SCImago Journal Rankings: 6.883
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorLiu, M-
dc.contributor.authorYan, Q-
dc.contributor.authorSun, Y-
dc.contributor.authorNam, Y-
dc.contributor.authorHu, L-
dc.contributor.authorLoong, JHC-
dc.contributor.authorOuyang, Q-
dc.contributor.authorZhang, Y-
dc.contributor.authorLi, HL-
dc.contributor.authorKong, FE-
dc.contributor.authorLi, L-
dc.contributor.authorLI, Y-
dc.contributor.authorLi, MM-
dc.contributor.authorCheng, W-
dc.contributor.authorJiang, LX-
dc.contributor.authorFang, S-
dc.contributor.authorYANG, XD-
dc.contributor.authorMo, JQ-
dc.contributor.authorGong, YF-
dc.contributor.authorTang, YQ-
dc.contributor.authorLi, Y-
dc.contributor.authorYuan, YF-
dc.contributor.authorMa, NF-
dc.contributor.authorLin, G-
dc.contributor.authorMa, S-
dc.contributor.authorWang, JG-
dc.contributor.authorGuan, XY-
dc.date.accessioned2020-08-07T09:02:33Z-
dc.date.available2020-08-07T09:02:33Z-
dc.date.issued2020-
dc.identifier.citationProceedings of the National Academy of Sciences, 2020, v. 117 n. 11, p. 6103-6113-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/284782-
dc.descriptioneid_2-s2.0-85081702329-
dc.description.abstractClinical observation of the association between cancer aggressiveness and embryonic development stage implies the importance of developmental signals in cancer initiation and therapeutic resistance. However, the dynamic gene expression during organogenesis and the master oncofetal drivers are still unclear, which impeded the efficient elimination of poor prognostic tumors, including human hepatocellular carcinoma (HCC). In this study, human embryonic stem cells were induced to differentiate into adult hepatocytes along hepatic lineages to mimic liver development in vitro. Combining transcriptomic data from liver cancer patients with the hepatocyte differentiation model, the active genes derived from different hepatic developmental stages and the tumor tissues were selected. Bioinformatic analysis followed by experimental assays was used to validate the tumor subtype-specific oncofetal signatures and potential therapeutic values. Hierarchical clustering analysis revealed the existence of two subtypes of liver cancer with different oncofetal properties. The gene signatures and their clinical significance were further validated in an independent clinical cohort and The Cancer Genome Atlas database. Upstream activator analysis and functional screening further identified E2F1 and SMAD3 as master transcriptional regulators. Small-molecule inhibitors specifically targeting the oncofetal drivers extensively down-regulated subtype-specific developmental signaling and inhibited tumorigenicity. Liver cancer cells and primary HCC tumors with different oncofetal properties also showed selective vulnerability to their specific inhibitors. Further precise targeting of the tumor initiating steps and driving events according to subtype-specific biomarkers might eliminate tumor progression and provide novel therapeutic strategy.-
dc.languageeng-
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org-
dc.relation.ispartofProceedings of the National Academy of Sciences-
dc.rightsProceedings of the National Academy of Sciences. Copyright © National Academy of Sciences.-
dc.subjecthepatocyte differentiation-
dc.subjectoncofetal properties-
dc.subjectliver development-
dc.subjectoncogenic driver-
dc.subjectcancer-
dc.titleA hepatocyte differentiation model reveals two subtypes of liver cancer with different oncofetal properties and therapeutic targets-
dc.typeArticle-
dc.identifier.emailYan, Q: yqw1014@hku.hk-
dc.identifier.emailLi, L: lilei728@hku.hk-
dc.identifier.emailMa, S: stefma@hku.hk-
dc.identifier.emailGuan, XY: xyguan@hku.hk-
dc.identifier.authorityMa, S=rp00506-
dc.identifier.authorityGuan, XY=rp00454-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.1912146117-
dc.identifier.pmid32123069-
dc.identifier.pmcidPMC7084088-
dc.identifier.scopuseid_2-s2.0-85081702329-
dc.identifier.hkuros312312-
dc.identifier.volume117-
dc.identifier.issue11-
dc.identifier.spage6103-
dc.identifier.epage6113-
dc.publisher.placeUnited States-

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