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GPNMB+Gal-3+ Hepatic Parenchymal Cells Promote Immunosuppressive Microenvironment Formation and Hepatocellular Carcinogenesis

ABSTRACT: Hepatocellular carcinoma (HCC) involves a multistep pathological process in which heterogenous cells are evolved to shape an immunosuppressive microenvironment. Yet it remains largely unknown regarding the specific cell populations and their evolving routes essential for HCC development. Here, we created a rat model mimicking human HCC and generated a single-cell resolution atlas to HCC development. Specifically, we identified three populations of hepatic parenchymal cells during HCC progression, i.e., metabolic hepatocyte (HC Meta ), hepatic progenitor cell-like population with differentiation potential (HPC-like Diff ) and immunosuppressive malignant transformation subset (H-M Immu ). These three distinct subpopulations formed an oncogenic trajectory depicting a dynamic landscape of hepatocyte carcinogenesis, with signature genes reflecting the transition from HPC-like Diff to H-M Immu . Cross-species comparative analysis further revealed the H-M Immu subset to be highly conserved. Importantly, the H-M Immu (GPNMB + Gal-3 + ) cells exhibit both malignant and immunosuppressive properties. Moreover, SOX18 was found to be required for the generation of GPNMB + Gal-3 + H-M Immu cells and for their ability to form tumors. Enrichment of GPNMB + Gal-3 + H-M Immu subset was found to be associated with poor prognosis and higher rate of recurrence for HCC patients. Collectively, we unraveled the single-cell evolving mechanism of HCC and uncovered GPNMB + Gal-3 + H-M Immu cells as a major subset contributing to the immunosuppressive microenvironment and HCC malignance

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE218561 | GEO | 2023/08/10

REPOSITORIES: GEO

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Project description:An integrative transcriptomics analysis was performed to evaluate the clinical relevance of genes associated with hepatocyte differentiation in human hepatocellular carcinoma (HCC). The well-established HepaRG cell line model was used to define a gene expression signature reflecting the status of tumor hepatocyte differentiation. This signature was able to stratify HCC patients into clinically relevant molecular subtypes. Then, a minimal subset of 7 differentiation-associated genes was identified to predict a poor prognosis in several cancer datasets. Hepatocellular carcinoma (HCC) is a deadly cancer worldwide as a result of a frequent late diagnosis which limits the therapeutic options. Tumor progression is correlated with a dedifferentiation of hepatocytes, the main parenchymal cells in the liver. Here, we hypothesized that the level of expression of genes reflecting the differentiation status of tumor hepatocytes could be clinically relevant in defining subsets of patients with variable clinical outcomes. To test this hypothesis, an integrative transcriptomic approach was used to stratify a cohort of 139 HCC patients based on a gene expression signature established using a well-controlled in vitro model of tumor hepatocyte differentiation in HepaRG cell line. First, we validated the HepaRG model by identifying a robust gene expression signature associated with hepatocyte differentiation and liver metabolism. This signature was able to distinguish specific developmental stages in mice. More importantly, the signature identified a subset of human HCC associated with a poor prognosis and cancer stem cell features. By using an independent HCC dataset (TCGA), a minimal subset of 7 differentiation-related genes was shown to predict a reduced overall survival, not only in patients with HCC but also in other types of cancers (e.g. kidney, pancreas, skin). In conclusion, the study demonstrates that genes reflecting the differentiation status of tumor hepatocytes are clinically relevant for predicting the prognosis of HCC patients.

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GPNMB+Gal-3+ Hepatic Parenchymal Cells Promote Immunosuppressive Microenvironment Formation and Hepatocellular Carcinogenesis

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