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Genomic resemblance of mouse models to human hepatocellular carcinoma matogenous metastasis of ovarian cancer: Re-thinking mode of spread

ABSTRACT: Two groupsHepatocellular carcinoma (HCC) is a heterogeneous malignant disease with molecularly and clinically distinct subtypes discovered in genomic studies. Mouse models are commonly used as preclinical model to study hepatocarcinogenesis, but how well these models recapitulate molecular subtypes of human HCC is unclear. Thus, we aimed to correlate nine mouse HCC models with clinical subtypes of human HCC by systematically comparing their genomic data. By integrating nine molecularly and clinically defined genomic signatures for human HCC with genomic data from nine mouse HCC models, we identified the mouse models that best resembled subtypes of human HCC and determined the clinical relevance of each model. Mst1/2 KO, Sav1 KO, and SV40 T antigen mouse model best recapitulated poor prognostic subtypes of human HCC, whereas the Myc transgenic model best resembled human HCCs with more favorable prognoses. The Myc model was also significantly associated with activation of β-catenin. E2f1, E2f1/Myc, E2f1/Tgfa, and diethylnitrosamine (DENA)-induced models were heterogeneous and were unequally split to poor and favorable prognoses. Most interestingly, Mst1/2 KO and Sav1 KO models best resembles human HCC with hepatic stem cell characteristics. When we applied a genomic predictor for immunotherapy, the six-gene interferon-γ (IFNG6) score, Mst1/2 KO, Sav1 KO, SV40, and DEN models were predicted to be the least responsive to immunotherapy. Further analysis of immune checkpoint genes showed that high expression of immune inhibitory genes (Cd276 and Pvrl2) in Mst1/2 KO, Sav1 KO, SV40 and low expression of immune stimulatory genes (Cd86) in DENA model might be accountable for lack of predictive response to immunotherapy. Conclusion: Most of the mouse models effectively recapitulated molecular characteristics of human subtypes, including response to immunotherapy. of samples are included: 1.SKOV3-ip1 2.SKOV3-OM3. Gene expression profiles of SKOV3-OM3 cells were compared to that of parental SKOV3 ip1 cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE110627 | GEO | 2019/01/01

REPOSITORIES: GEO

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Project description:Background & Aims. Resection of hepatocellular carcinoma (HCC) tumors by partial hepatectomy (PHx) is associated with promoting hepatocarcinogenesis. We have previously reported that PHx promotes hepatocarcinogenesis in the Mdr2-knockout (Mdr2-KO) mouse, a model for inflammation-mediated HCC. Now, we explored the molecular mechanisms underlying the tumor-promoting effect of PHx in these mice. Methods. Using microarrays-based techniques, we compared genomic and transcriptomic profiles of HCC tumors developing in the Mdr2-KO mice either spontaneously or following PHx. Results. PHx accelerated HCC development in these mice by four months. PHx-induced tumors had only amplifications affecting multiple chromosomes and locating mainly near the acrocentric centromeres of murine chromosomes. Four different chromosomal regions were amplified each in at least three tumors. All tumors of untreated mice had chromosomal aberrations, including both deletions and amplifications. Comparison of gene expression profiles revealed a significantly enriched expression of oncogenes, chromosomal instability markers and E2F1 targets in the post-PHx compared to spontaneous tumors. Both tumor groups shared the same frequent amplification at chromosome 18. Here, we demonstrated that one of the regulatory genes encoded by this amplified region, Crem, was over-expressed in the nuclei of murine and human HCC cells in vivo, and that it stimulated proliferation of human HCC cells in vitro. Conclusions: PHx of a chronically inflamed liver directed tumor development to a discrete pathway characterized by amplification of specific chromosomal regions and expression of specific tumor-promoting genes. Crem is a new candidate HCC oncogene frequently amplified in this model and frequently over-expressed in human HCC. To explore the mechanisms of the accelerated HCC development by PHx, we compared liver tumors and their matched non-tumor liver tissues between 9-month-old hepatectomized and 13-14-month-old untreated Mdr2-KO mice.