CDX2 Tumor Suppressor Pathway Defects in Colon Cancer

描述（由申请人提供）：大多数结直肠癌（CRC）起源于腺瘤前体。累积的癌基因和肿瘤抑制基因（TSG）缺陷是腺瘤发展和某些病变进展为癌的基础。在肿瘤发生、发展和维持中起关键作用的基因缺陷被称为“驱动因子”。一个“乘客”的缺陷可能只是出现了与司机改变。解决CRC中的驾驶员和乘客缺陷可能需要深入的工作。即使对于成熟的TSG，它们在癌症过程中的作用往往仍然是谜。在前期，我们描述了新的CDX 2 P-Cre转基因小鼠及其用于盲肠、结肠和直肠中Apc TSG的体细胞失活，从而产生结肠腺瘤-癌进展的新模型。这些新型CDX 2 P-Cre转基因小鼠对于CRC中候选驱动基因的体细胞基因靶向具有很大的实用性。我们还产生了Cdx 2的条件性敲除，并发现结肠上皮中的Cdx 2失活产生有趣的基因剂量依赖性效应。这一竞争性更新申请的总体目标是确定CRC中基因病变的功能贡献，强调在小鼠结直肠上皮中选择的TSGs体细胞靶向的工作。具体目标是：I）确定Cdx 2缺陷在结肠肿瘤发生中的作用;和II）确定p53错义突变在促进结肠直肠腺瘤-癌进展中的作用。这些目标是由方法上的共性和测试CRC领域关键概念的目标统一起来的，例如多个基因缺陷如何在肿瘤进展中协作。除了提供CRC中选定TSGs的关键功能评估外，这些研究还应提供有关基因缺陷的新机制线索。结肠肿瘤模型也代表了一个新的方向，因为小肠肿瘤模型迄今为止在该领域的工作中占主导地位。

DESCRIPTION (provided by applicant): Most colorectal cancers (CRCs) arise from adenomatous precursors. Accumulated oncogene and tumor suppressor gene (TSG) defects underlie adenoma development and progression of some lesions to carcinoma. Gene defects with key roles in tumor initiation, progression, and maintenance are termed "drivers". A "passenger" defect might simply have arisen coincident with a driver alteration. Sorting out driver and passenger defects in CRC will likely require in-depth work. Even for well-established TSGs, their role in the cancer process often remains enigmatic. During the prior period, we described novel CDX2P-Cre transgenic mice and their use for somatic inactivation of the Apc TSG in cecum, colon and rectum, leading to new models of colonic adenoma-carcinoma progression. These novel CDX2P-Cre transgenic mice are of great utility for somatic gene targeting of candidate driver genes in CRC. We also generated a conditional knockout of Cdx2 and have found Cdx2 inactivation in colon epithelium yields interesting gene dosage-dependent effects. The overarching goal of this competing renewal application is to define the functional contribution of gene lesions in CRC, emphasizing work where selected TSGs are somatically targeted in mouse colorectal epithelium. The specific aims are: I) Define the contribution of Cdx2 defects in colon tumorigenesis; and II) Define the role of p53 missense mutations in promoting colorectal adenoma- carcinoma progression. The aims are united by commonalities in approach and the goal of testing key concepts in the CRC field, such as how multiple gene defects collaborate in tumor progression. Besides providing a key functional assessment of selected TSGs in CRC, the studies should offer new mechanistic clues about the gene defects. The colon tumor models also represent a new direction, as small intestinal tumor models have dominated work in the field to date.