Mutant mouse models of exocrine pancreatic cancer

描述(申请人提供)：导管型胰腺癌几乎都是致命的，在早期阶段不能有效地发现。几乎所有胰腺癌和癌前导管增生症的病例都含有致癌基因Kras突变，这表明它在这种疾病中的重要性。癌症动物模型忠实地概括了相似的人类情况，为探索癌症的分子基础、开发早期检测策略和评估新的治疗方法提供了机会。虽然之前已经描述了易患外分泌型胰腺癌的突变小鼠，但没有一只小鼠患上与人类疾病相似的导管型胰腺癌。为了构建更相关的导管胰腺癌小鼠模型，我们设计了一种突变的小鼠品系，该品系含有内源性的、有条件表达的、致癌的K-ras G12D等位基因。通过将该菌株与在胰腺中表达Cre重组酶的小鼠菌株杂交，我们观察到了与人类惊人相似的癌前胰腺导管病变(PanlN)。在这里，我们将研究能够启动胰腺癌的细胞间隔，确定INK4a/ARF基因中两个抑癌基因在肿瘤进展中的相对重要性，并评估Notch信号和MMP7功能在PanlN和PDA发生中的作用。合适的小鼠胰腺导管腺癌模型的可获得性将允许详细评估在肿瘤发生的不同阶段存在的分子和细胞特征。这样的研究在人类胰腺癌标本中基本上是不可能的，因为它们总是在非常晚期才被发现。从这个小鼠模型中获得的信息应该有助于进一步了解人类胰腺癌。

DESCRIPTION (provided by applicant): Ductal pancreatic adenocarcinoma is almost uniformly lethal and cannot be effectively detected at early stages. Virtually all cases of pancreatic cancer and preneoplastic ductal hyperplasias contain oncogenic Kras mutations, suggesting its importance in this disease. Animal models of cancer that faithfully recapitulate the cognate human condition afford the opportunity to explore the molecular basis of cancer, develop early detection strategies, and evaluate novel therapies. Although mutant mice predisposed to the development of exocrine pancreatic cancer have been previously described, none develop ductal pancreatic adenocarcinoma resembling the human disease. In order to construct a more relevant murine model of ductal pancreatic cancer, we have engineered a mutant mouse strain that harbors an endogenous, conditionally-expressed, oncogenic K-ras G12D allele. By crossing this strain with mouse strains that express Cre recombinase in the pancreas, we observe preneoplastic pancreatic ductal lesions (PanlN) that strikingly resemble those seen in humans. Here, we will investigate the cellular compartments that are capable of initiating pancreatic cancer, determine the relative importance of the two tumor suppressor genes in the Ink4a/ARF locus with regards to tumor progression, and evaluate the role of Notch signaling and MMP7 function in the development of PanlN and PDA. The availability of a suitable murine model of pancreatic ductal adenocarcinoma will allow a detailed assessment of the molecular and cellular features present in discrete stages of tumorigenesis. Such studies are essentially impossible in human pancreatic cancer specimens since they are invariably detected only at very late stages. Information gained from this murine model should facilitate further understanding of human pancreatic cancer.