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

 描述（由申请人提供）：最近提出了卵巢癌（OvCa）发病机制的二元模型，其中OvCas可大致分为两类。I型OvCas被认为是低级别的，相对惰性的肿瘤，而II型OvCas从一开始就是高级别的，生物侵袭性的肿瘤。最近的研究表明，最常见和致命类型的“卵巢”癌，高级别浆液性癌（HGSC），通常发生在输卵管上皮（FTE），而不是卵巢表面上皮（OSE）。HGSC显示出高水平的染色体不稳定性，并且几乎所有的HGSC都具有体细胞TP 53突变，其在HGSC发病的非常早期发生。RB和BRCA途径的功能障碍在HGSC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HGSC的女性在诊断时通常具有小的原发病灶和广泛的转移灶。目前的挑战是检测早期HGSC，而它们可以通过手术切除来治愈。OvCa的基因工程小鼠模型（GEMM）与其人类肿瘤对应物密切相关，提供了极好的体内系统，用于研究肿瘤生物学和进行临床前研究，旨在改善OvCa的预防、早期检测和治疗。已经开发了几种基于OSE转化的OvCa GEMM并用于翻译研究。最近，一些模型的基础上转换的全职员工已被报道。目前尚不清楚OvCa的输卵管（小鼠输卵管）模型是否上级OSE产生的模型，因为它们在多大程度上重现了人OvCas的生物学或它们在翻译应用中的效用。我们已经开发了一种新的GEMM，采用Ovgp 1启动子来指导他莫昔芬（TAM）诱导的Cre重组酶在FTE中的表达。Ovgp 1-iCreERT 2小鼠也携带在卵巢类卵巢癌（OEC，原型I型肿瘤）和HGSC（原型II型肿瘤）中特征性失活的肿瘤抑制基因的floxed等位基因，在用TAM治疗后，该小鼠可被诱导在FTE中形成肿瘤，或在卵巢囊注射表达Cre的腺病毒后，在OSE中产生肿瘤。这个资助机会的总体目标是提高小鼠模型在转化研究中的适用性。为此，我们将追求以下具体目的：1）证明由FTE转化产生的OvCa的GEMM在其与人OvCa对应物的形态学和分子相似性方面上级由OSE转化产生的那些;和2）测试用于基于宫颈-阴道灌洗（鼠Pap试验）早期检测输卵管HGSC的新工具菌株。全面的基因表达和突变数据以及小鼠OEC和HGSC的匹配高分辨率数字图像将通过NCIP Hub平台在肿瘤模型论坛上共享。

 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.