Mutant mouse models of exocrine pancreatic cancer

描述（由申请人提供）：导管胰腺腺癌几乎都是致命的，在早期阶段无法有效检测。几乎所有的胰腺癌和癌前导管增生病例都含有致癌的Kras突变，提示其在该疾病中的重要性。癌症的动物模型忠实地再现了同源的人类状况，为探索癌症的分子基础、制定早期检测策略和评估新疗法提供了机会。虽然突变小鼠易患外分泌胰腺癌，但没有发生类似人类疾病的导管胰腺腺癌。为了构建更相关的小鼠导管性胰腺癌模型，我们设计了一种突变小鼠菌株，该菌株含有内源性、条件表达的致癌K-ras G12D等位基因。通过将该菌株与胰腺中表达Cre重组酶的小鼠菌株杂交，我们观察到肿瘤前胰腺导管病变（PanlN）与人类的病变非常相似。在这里，我们将研究能够启动胰腺癌的细胞区室，确定Ink4a/ARF基因座中两个肿瘤抑制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发展中的作用。合适的胰腺导管腺癌小鼠模型的可用性将允许对肿瘤发生的离散阶段存在的分子和细胞特征进行详细评估。这样的研究基本上不可能在人类胰腺癌标本中进行，因为它们总是在很晚的阶段才被发现。从该小鼠模型中获得的信息将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.