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

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. Nine genetically engineered or chemically induced mouse HCC models were used in this study. Total of 108 HCC tumors were collected for the study. Tumors from transgenic mice expressing myelocytomatosis oncogene (Myc) (n = 15), Myc/transforming growth factor alpha (Tgfa) (n = 15), E2F transcription factor 1 (E2f1) (n = 18), or Myc/E2f1 (n = 15) were carried out microarray experiment. The diethylnitrosamine (DEN)-induced model (n = 16), simian vacuolating virus 40 (SV40) T-antigen transgenic model (n = 10), Mst1/2 double KO (n = 4) and Sav1 KO (n = 11) mouse models were used for screening.