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

 描述(申请人提供)：最近提出了一种卵巢癌发病机制的二元模型，其中卵巢癌大致可分为两类。I型OvCas被认为是低级别、相对无痛的肿瘤，而II型OvCas从一开始就是高级别的、具有生物学侵袭性的肿瘤。最近的研究表明，最常见和最致命的卵巢癌类型，高度浆液性癌(HGSC)，通常发生在输卵管上皮(FTE)而不是卵巢表面上皮(OSE)。HGSC表现出高度的染色体不稳定性，几乎所有的HGSC都存在体细胞TP53突变，这种突变发生在HGSC发病的非常早期。Rb和BRCA通路的功能障碍在HGSCs中也很常见。早期病变的遗传不稳定性可能会增加获得转移潜能的体细胞突变的可能性。因此，患有HGSCs的妇女在确诊时通常有小的原发病灶和广泛的转移。目前的一个挑战是在可以通过手术切除治愈的情况下发现早期HGSCs。OvCa的基因工程小鼠模型(GEMM)与人类肿瘤模型非常相似，为研究肿瘤生物学和执行旨在改进OvCa的预防、早期发现和治疗的临床前研究提供了极好的体内系统。一些基于OSE转换的OvCa的GEMM已经被开发出来并用于翻译研究。最近，有几个基于FTE转型的模型被报道。目前尚不清楚Ovca的输卵管(小鼠输卵管)模型在概括人类OvCas的生物学特性或用于翻译应用方面是否优于OSE模型。我们开发了一种新的GEMM，它利用Ovgp1启动子在FTE中直接表达三苯氧胺()诱导的Cre重组酶。Ovgp1-iCreERT2小鼠同时携带在卵巢子宫内膜样癌(OEC，典型的I型肿瘤)和HGSC(典型的II型肿瘤)中典型失活的肿瘤抑制基因的丛状等位基因，经治疗后，可在FTE区诱导形成肿瘤，或在卵巢法氏囊注射表达Cre的腺病毒后，在OSE区形成肿瘤。这一资助机会的首要目标是提高小鼠模型在翻译研究中的适用性。为此，我们将追求以下具体目标：1)证明FTE转化产生的OvCa的GEMM在形态和分子上与人类OvCa转化产生的GEMM相比优于OSE转化产生的GEMM；以及2)测试一种基于宫颈-阴道灌洗(小鼠巴氏试验)早期检测输卵管HGSCs的新工具菌株。全面的基因表达和突变数据以及匹配的小鼠嗅鞘细胞和HGSCs的高分辨率数字图像将通过NCIP Hub平台在肿瘤学模型论坛上共享。

 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.