High-grade serous ovarian cancer induced in different sites of origin in mice exemplifies diverse features of the human disease

We have developed novel genetically engineered mouse models for high-grade serous carcinoma of the ovary. We compare expression profiles of 4 different models for HGSC, one developing carcinoma from the ovarian surface epithelium (OSE) and 3 others that develop carcinoma from Fallopian tube epithelium (FTE). FTE-originating cancer models utilize either Pax8- or Ovgp1-promotor driven expression of inducible Cre recombinase (CreERT2) and the last model utilizes direct injection of adeno-virus expressing Cre recombinase into oviducts to induce the desired genetic aberrations: loss of Brca1, loss or mutation (R172H) of Trp53 and inhibition of proteins of the Rb family (via expression of K18GT121 transgene). We compare tumors from genetically engineered mouse models (GEMMs) and from GEM-derived allografts and compare them to corresponding normal tissue: ovary or oviduct (mouse equivalent of Fallopian tube). Expression profiling allowed us to investigate molecular subtypes of HGSC in these models and comparison to human HGSC.These well-defined, tractable models represent a valuable resource for assessing novel drugs and immunotherapies for patients with HGSC. Overall design: OSE-BPR=model developing carcinoma from the ovarian surface epitheium. Genetic aberrations (loss of Brca1, loss of Trp53 and Rb inhibition) were induced by injection of adeno-Cre under ovarian bursa of the genetically engineered mice with a complex genotype Brca1 fl/fl, Trp53 fl/fl, K18GT121 Tg/+. Ad-BPR=model developing carcinoma from the oviductal epithelium. Genetic aberrations (loss of Brca1, loss of Trp53 and Rb inhibition) were induced by injection of adeno-Cre into the oviducts of the genetically engineered mice with a complex genotype Brca1 fl/fl, Trp53 fl/fl, K18GT121 Tg/+. Pax8-BPR=model developing carcinoma from the oviductal epithelium utilizing Pax8-CreERT2 transgene to direct the expression of Cre in the secretory cells of the oviductal epithelium. Genetic aberrations (loss of Brca1, loss of Trp53 and Rb inhibition) were induced by tamoxifen treatment of the genetically engineered mice with a complex genotype Brca1 fl/fl, Trp53 fl/fl, K18GT121 Tg/+, Pax8-CreERT2 Tg/+. Ovgp1-BPR= model developing carcinoma from the oviductal epithelium utilizing Ovgp1-iCreERT2 transgene to direct the expression of Cre in the secretory cells of the oviductal epithelium. Genetic aberrations (loss of Brca1, Trp53 mutaion R172H and Rb inhibition) were induced by tamoxifen treatment of the genetically engineered mice with a complex genotypeBrca1 fl/fl, Trp53 fl/fl, K18GT121 Tg/+, Ovgp1-iCreERT2 Tg/+.All tumors were harvested at endpoint (multiple month post induction)