Understanding initiation and progression of IPMNs in pancreatic cancer

项目摘要 胰腺导管腺癌(PDAC)是一种致命的疾病，存活率仅为10%，主要是 因为大多数患者是在癌症扩散到胰腺以外之后才被诊断出来的。PDAC被认为是 起源于两种类型的非侵袭性癌前病变，即胰腺上皮内瘤变(Panins)， 和导管内乳头状黏液性肿瘤(IPMN)，发生在胰腺的导管上皮。 在这里，IPMN是大的囊性肿瘤，偶然发现的频率通过 腹部成像。全面的基因组分析表明，激活KRAS、GNAS和 PI3KCA与IPMN的发病有关。尽管转基因小鼠模型(GEMM) 为IPMN的发展提供了一些见解，IPMN是如何在人类 仅在IPMN病变中发现的突变(GNAS和PIK3CA)以及合作事件促进了什么 进展为癌症的原因尚不清楚。为了解决这个问题，我们开发了一个强大的平台来 从人类胚胎干细胞(HESC)来源的胰腺前体细胞中产生导管和腺泡类器官。 利用人的外分泌胰腺，我发现GNASR201C在人的导管器官中的表达 概述了IPMN的几个特征，包括管腔扩张和粘蛋白分泌，如MUC2。这 一项研究旨在验证致癌GNAS通过不依赖PKA促进细胞增殖的假设 在导管细胞中的机制，并与其他遗传事件合作，促进糖尿病的发生和发展 IPMN在体内的损伤。结合细胞生物学、蛋白质组学和原位移植方法， 这项建议旨在确定致癌的GNAS对细胞的差异调节机制 在胰腺导管和腺泡类器官中的增殖(Aim1)；并探索通过 致癌GNAS促进IPMN和IPMN来源的PDAC的形成 准确的组织环境(目标2和3)。预期结果将提供对来源细胞的深入了解 IPMN损害；确定GNAS促进早期损害的机制；以及建立IPMN模型- 衍生的PDAC，可长期用于治疗广泛的IPMN相关的 肿瘤。K22奖项将允许参与实验室管理、指导和赠款撰写 讲习班和参加授课课程，这将为我提供必要的知识和资源 和培训，以(A)了解组学研究的原理；(B)建立小鼠癌症模型；以及(C)申请 融资(R01)机会。加上我的合作者的支持和建立一个咨询 在获得教员职位后，我的全面研究、培训和职业发展将对我有所帮助 作为独立的研究人员，在胰腺癌研究中建立独特的利基市场。

Project Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a dismal survival rate at just 10%, largely because most patients are diagnosed after the cancer has spread beyond the pancreas. PDAC is thought to arise from two types of noninvasive precancerous lesions, namely, pancreatic intraepithelial neoplasia (PanINs), and intraductal papillary mucinous neoplasms (IPMN), that develop in the ductal epithelium of the pancreas. Here, IPMNs are large cystic neoplasms that are incidentally detected at increasing frequencies through abdominal imaging. Comprehensive genomic analyses indicate that activating mutations in KRAS, GNAS, and PI3KCA are associated with IPMN pathogenesis. Although genetically engineered mouse models (GEMMs) have provided some insights into the development of IPMN, how IPMNs arise in humans in the context of mutations that are exclusively found in IPMN lesions (GNAS and PIK3CA) and what cooperating events promote progression to carcinoma is not understood. To address this question, we have developed a robust platform to generate ductal and acini organoids from human embryonic stem cell (hESC)-derived pancreatic progenitor cells. Using human exocrine pancreas, I have found that expression of GNASR201C in human ductal organoids recapitulates several features of IPMN including lumen expansion, and secretion of mucins such as MUC2. This study sets out to test the hypothesis that oncogenic GNAS promotes cell proliferation through PKA-independent mechanisms in ductal cells and cooperates with other genetic events to promote initiation and progression of IPMN lesions in vivo. Using a combination of cell biology, proteomics, and orthotopic transplantation approaches, this proposal aims to identify mechanisms through which oncogenic GNAS differentially regulates cell proliferation in ductal and acini pancreatic organoids (Aim1); and explore additional genetic events through which oncogenic GNAS promotes formation of IPMN and IPMN-derived PDAC in the context of a physiologically accurate tissue environment (Aim 2 and 3). The expected results will provide insights into the cell of origin for IPMN lesions; identify mechanisms by which GNAS promotes early lesions; and establish models of IPMN- derived PDAC, which may be exploited therapeutically in the long term to treat a broad range of IPMN-associated tumors. The K22 award will allow participation in laboratory management, mentorship and grant writing workshops, and enrolment in didactic courses, that will provide me with the necessary knowledge, resources and training to (a) understand principles of omics research; (b) model cancer in mice; and (c) apply for additional funding (R01) opportunities. Together with the support of my collaborators and establishment of an advisory committee after obtaining a faculty position, my overall research, training and career development will help me establish a unique niche in pancreatic cancer research as an independent investigator.