Credentialing Ovarian Cancer Models in the Context of the Dualistic Pathway Paradigm

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 DESCRIPTION (provided by applicant): A dualistic model of ovarian cancer (OvCa) pathogenesis has recently been proposed in which OvCas can be broadly divided into two categories. Type I OvCas are considered to be low-grade, relatively indolent tumors, while Type II OvCas are high-grade, biologically aggressive tumors from their outset. Recent studies suggest the most common and lethal type of "ovarian" cancer, high-grade serous carcinoma (HGSC), usually arises in fallopian tube epithelium (FTE) rather than the ovarian surface epithelium (OSE). HGSCs display a high level of chromosomal instability and virtually all harbor somatic TP53 mutations, which occur very early in HGSC pathgenesis. Dysfunction of the RB and BRCA pathways is also common in HGSCs. Genetic instability in the early lesions presumably enhances the likelihood that somatic mutations conferring metastatic potential will be acquired. Thus, women with HGSCs typically have small primary lesions and widespread metastases at diagnosis. A current challenge is to detect early-stage HGSCs while they are curable with surgical resection. Genetically engineered mouse models (GEMMs) of OvCa that closely recapitulate their human tumor counterparts provide excellent in vivo systems with which to study tumor biology and perform pre-clinical studies aimed at improving prevention, early detection, and therapy for OvCa. Several GEMMs of OvCa based on OSE transformation have been developed and used in translational studies. More recently, a few models based on transformation of the FTE have been reported. It is not yet known whether oviductal (mouse fallopian tube) models of OvCa are superior to those arising from the OSE with respect to how well they recapitulate the biology of human OvCas or their utility for translational applications. We have developed a new GEMM that employs the Ovgp1 promoter to direct expression of Tamoxifen (TAM)-inducible Cre recombinase in the FTE. Ovgp1-iCreERT2 mice that also carry floxed alleles of tumor suppressor genes that are characteristically inactivated in ovarian endometrioid carcinoma (OEC, prototypical Type I tumor) and HGSC (prototypical Type II tumor) can be induced to form tumors in the FTE following treatment with TAM, or tumors arising in the OSE following ovarian bursal injection of adenovirus expressing Cre. The overarching goal of this funding opportunity is to enhance applicability of mouse models for translational research. Toward that end, we will pursue the following Specific Aims: 1) To credential GEMMs of OvCa arising from FTE- transformation as superior to those arising from OSE-transformation in terms of their morphological and molecular similarity to their human OvCa counterparts; and 2) To test a new tool strain for early detection of oviductal HGSCs based on cervical-vaginal lavage (murine Pap test). Comprehensive gene expression and mutation data with matched high-resolution digital images of murine OECs and HGSCs will be shared at the Oncology Models Forum via the NCIP Hub platform.