Molecular and Cellular Origins of Pancreatic Cancer

描述（由申请人提供）：本提案的目的是通过使用基因定义的小鼠模型来研究胰腺导管腺癌（PDA）的分子和细胞起源。首席研究员苏尼尔·r·辛戈拉尼（Sunil R. Hingorani）博士是一名内科科学家，他的长期兴趣是将基础研究发现应用于改善胰腺癌患者的护理。现在，在这个国家，PDA是癌症相关死亡的第四大原因，它的发病率和死亡率都在上升。这里所描述的工作的基本前提是，全面了解这种疾病的发病机制需要生成动物模型，这些模型忠实地概括了从最早的侵袭前状态开始的整个进展方案。事实上，考虑到这种疾病在病程早期就有转移的倾向，有意义的干预能力可能需要从一开始就进行识别和治疗。通过将内源性Kras（G12D）表达靶向于发育中的小鼠胰腺祖细胞，已经产生了一种小鼠品系，可以准确地模拟胰腺上皮内瘤变（PanlNs）的所有三个阶段，PanlNs被认为是侵袭性胰腺癌的前兆。这些病变自发发展为浸润性和转移性导管腺癌，明确表明panln确实是PDA的前体。因此，第一个目的是研究内源性Kras（G12D）表达诱导PanIN病变形成的分子机制。其次，研究致癌Kras与肿瘤抑制基因p53特异性点突变协同加速胰腺癌发展的机制。最后，PDA的起源细胞将通过靶向条件Kras（G12D）表达到胰腺的离散细胞区室来鉴定。我们可以合理地希望，从这些努力中收集到的见解将有助于开发有效的早期检测方法，识别和测试高风险患者的化学预防策略，并为早期甚至晚期疾病设计潜在的治疗方法。NCI胰腺癌进展审查小组报告将基于基因的疾病动物模型的发展确定为研究重点。本应用程序中描述的研究专门解决了这一优先事项，并且与胰腺癌100%相关。

DESCRIPTION (provided by applicant): The objectives of this proposal are to investigate the molecular and cellular origins of pancreatic ductal adenocarcinoma (PDA) through the use of genetically defined mouse models. The principal investigator, Dr. Sunil R. Hingorani, is a physician-scientist whose longterm interests are in applying fundamental research discoveries toward the improved care of pancreatic cancer patients. Now the fourth leading cause of cancer-related deaths in this country, PDA is a disease with a rising incidence and unabated mortality. The underlying premise of the efforts described here holds that a comprehensive understanding of the pathogenesis of this disease requires the generation of animal models that faithfully recapitulate the entire progression scheme beginning with the earliest preinvasive state. Indeed, given the penchant for this disease to metastasize very early in its course, the ability to intervene meaningfully likely requires identification and treatment from its very inception. By targeting endogenous Kras(G12D) expression to progenitor cells of the developing mouse pancreas, a strain of mice has been generated that accurately models all three stages of pancreatic intraepithelial neoplasias (PanlNs), the presumptive precursors to invasive pancreatic cancer. These lesions spontaneously progress to invasive and metastatic ductal adenocarcinoma, demonstrating unequivocally that PanlNs are indeed precursors to PDA. Thus, the first aim is to study the molecular mechanisms by which endogenous Kras(G12D) expression induces the formation of PanIN lesions. Second, the mechanisms by which oncogenic Kras cooperates with a specific point-mutation of the p53 tumor suppressor gene to hasten the development of pancreatic cancer will be investigated. Finally, the cell-of-origin for PDA will be identified by targeting conditional Kras(G12D) expression to discrete cellular compartments of the pancreas. It can be reasonably hoped that the insights gleaned from these endeavors will aid efforts to develop effective early detection methods, identify and test chemopreventive strategies for high-risk patients, and devise potential therapies for early and even advanced stage disease. The NCI Pancreatic Cancer Progress Review Group Report identified the development of gene-based animal models of the disease as a research priority. The research described in this application specifically addresses this priority and is 100% relevant to pancreatic cancer.