A hepatocyte differentiation model reveals two subtypes of liver cancer with different oncofetal properties and therapeutic targets
- 2 March 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (11), 6103-6113
- https://doi.org/10.1073/pnas.1912146117
Abstract
Clinical 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.Keywords
Funding Information
- National Natural Science Foundation of China (81272416)
- National Natural Science Foundation of China (81702400)
This publication has 50 references indexed in Scilit:
- Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinomaNature Medicine, 2013
- The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics DataCancer Discovery, 2012
- Hepatocellular CarcinomaThe New England Journal of Medicine, 2011
- A Myc Network Accounts for Similarities between Embryonic Stem and Cancer Cell Transcription ProgramsCell, 2010
- SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomasNature Genetics, 2009
- Integrative Transcriptome Analysis Reveals Common Molecular Subclasses of Human Hepatocellular CarcinomaCancer Research, 2009
- EpCAM-Positive Hepatocellular Carcinoma Cells Are Tumor-Initiating Cells With Stem/Progenitor Cell FeaturesGastroenterology, 2009
- Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemiaNature, 2009
- An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumorsNature Genetics, 2008
- MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancerNature, 2004