CDX2 Tumor Suppressor Pathway Defects in Colon Cancer

描述(申请人提供)：大多数结直肠癌(CRC)起源于腺瘤前体瘤。累积的癌基因和肿瘤抑制基因(TSG)缺陷是腺瘤发生和某些病变进展为癌的原因。在肿瘤的发生、发展和维持中起关键作用的基因缺陷被称为“驱动因素”。“乘客”缺陷可能只是与司机变更同时出现的。解决CRC中的司机和乘客缺陷可能需要深入的工作。即使对于久负盛名的TSG，它们在癌症过程中的作用往往仍然是个谜。在此之前，我们描述了新型CDX2P-Cre转基因小鼠及其在盲肠、结肠和直肠APC TSG体细胞失活方面的应用，从而导致了结肠腺瘤-癌进展的新模型。这些新型CDX2P-Cre转基因小鼠在结直肠癌候选驱动基因的体细胞基因打靶方面具有重要的应用价值。我们还产生了有条件的CDX2基因敲除，并发现在结肠上皮中CDX2的失活产生了有趣的基因剂量依赖效应。这一竞争性更新应用的首要目标是定义结直肠癌中基因损伤的功能贡献，强调选定的TSG在小鼠结肠上皮中的躯体靶向工作。其具体目的是：1)确定CDX2缺陷在结肠癌发生中的作用；2)确定P53错义突变在促进结直肠腺瘤-癌进展中的作用。这些目标由方法上的共性和测试CRC领域的关键概念的目标统一起来，例如多个基因缺陷如何在肿瘤进展中协同作用。除了提供对结直肠癌中选定的TSG的关键功能评估外，这些研究还应该提供关于基因缺陷的新的机制线索。结肠肿瘤模型也代表了一个新的方向，因为到目前为止，小肠肿瘤模型主导了该领域的工作。

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.