Single cell analysis reveals cancer cell heterogeneities in hepatocellular carcinoma [SMART-seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE103866 | GEO | 2018/06/11
REPOSITORIES: GEO
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Project description:Combined transcriptomic and functional analyses of HCC cells at single-cell level were performed to assess CSC heterogeneity.
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Project description:Clinical heterogeneity of hepatocellular carcinoma (HCC) reflected in unequal outcome of treatment is poorly defined in molecular level, and molecular subtypes and their associated biomarkers have not been established to improve prognostification and treatment of HCC. Using microarray technologies, we analyzed gene expression profiling data from HCC patients, uncovered mesenchymal subtype, and identified gene expression signature associated with mesenchymal phenotype of HCC.
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Project description:Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death worldwide. Like in many cancers, tumor heterogeneity in HCC hampers the development of personalized therapies. Integrative genomics contributed to characterize HCC subtypes by identifying specific genetic alterations and molecular signatures, leading to targeted drug candidates. However, no consensus was achieved for genes and pathways recurrently altered in HCC. Here, a meta-analysis of 15 independent HCC datasets identifies a comprehensive signature consisting of 935 genes commonly deregulated in HCC as compared to the surrounding non-tumor tissue (P<0.01). The 935-gene HCC signature covers well-established cancer hallmarks (e.g. proliferation, metabolic reprogramming, microenvironment remodeling) together with specific hallmarks associated with protein turnover and epigenetics. Accordingly, the 935-gene HCC signature highlights relevant drugs for systemic therapies, including including two histone deacetylase (HDAC) inhibitors (trichostatin A and vorinostat), PI3K inhibitor LY294002, mTOR inhibitor sirolimus (also known as rapamycin), alpha-estradiol and resveratrol. The impact of these drugs as compared to sorafenib that is currently used for the treatment of advanced HCC was evaluated on the viability of 6 HCC-derived cell lines. We concluded that combined therapies targeting common and subtype-specific cancer networks may represent a relevant strategy to efficiently treat liver cancer.
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Project description:Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Understanding of the intratumoral heterogeneity of HCC is instructive for developing personalized therapy and molecular biomarkers. We applied whole exome sequencing to a total of 63 samples from 11 patients to resolve the genetic architecture and subclonal diversification. Notably, spatial genomic diversity was found in all 11 HCC cases, with 33% of the driver mutations being heterogeneous. Temporal dissection of mutational signatures suggested that exogenous and endogenous factors have different contributions in shaping the mutational spectrum during the development of HCC. Moreover, we observed extensive intratumoral epigenetic heterogeneity in HCC, and showed that integrative analysis of both genetic and epigenetic phylogenies could generate more robust resolution of clonal architecture than single profiling approach. Our results also demonstrated prominent epigenetic subclonal diversification even in a stable HCC genome. Together, these findings highlight the widespread intratumoral heterogeneity at both genomic and epigenomic levels in HCC, and provide important molecular foundation for better understanding of the biology and pathogenesis of this malignancy.
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Project description:To explore the target genes of long noncoding RNA lncTCF7, we established lncTCF7-silenced HCC primary CSC cells and conducted transcriptome microarray analysis. We used microarrays to identify distinct gene expression underlying shCtrl and shlncTCF7 of hepatocellular carcinoma sample stem cells.
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