Understanding initiation and progression of IPMNs in pancreatic cancer

了解胰腺癌中 IPMN 的起始和进展

• 批准号: 10351395
• 负责人: Ridhdhi R Desai
• 金额: $ 19.44万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10351395
• 关键词: Abdomen; Acinus organ component; Address; Advisory Committees; Age; Area; Binding; Biology; Biotinylation; Cancer Biology; Cancer Model; Carcinoma; Cell Proliferation; Cells; Cellular biology; Cyclic AMP-Dependent Protein Kinases; Cyst; Cystic Neoplasm; DNA Sequence Alteration; Data; Development; Diagnosis; Disease; Doxycycline; Duct (organ) structure; Ductal Epithelial Cell; Ductal Epithelium; Educational workshop; Environment; Epithelium; Event; Exocrine pancreas; Faculty; Frequencies; Funding; Funding Opportunities; Future; GTP-Binding Proteins; Genes; Genetic; Genetic Screening; Genetically Engineered Mouse; Genomics; Grant; Human; Image; Individual; Induced Mutation; Institution; K22 Award; KRAS2 gene; KRASG12D; Knowledge; Laboratories; Lesion; Libraries; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mentorship; Modeling; Mucin-2 Staining Method; Mucinous Neoplasm; Mucins; Mus; Mutation; Oncogenes; Oncogenic; Organoids; Other Genetics; PIK3CA gene; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatic duct; Papillary; Pathogenesis; Patients; Phase; Phenotype; Physiological; Positioning Attribute; Proteomics; Research; Research Personnel; Research Proposals; Resources; Secure; Signal Transduction; Supervision; Surface; Survival Rate; System; Testing; Therapeutic; Tissues; Training; Transplantation; Writing; anticancer research; career; career development; cell type; combinatorial; experience; human embryonic stem cell; human stem cells; in vivo; inhibitor; insight; islet stem cells; loss of function; older patient; pancreatic ductal adenocarcinoma cell; premalignant; small hairpin RNA; tumor

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.

项目摘要 胰腺导管腺癌（PDAC）是一种致命疾病，生存率较低，仅为10％，在很大程度上很大程度上 因为大多数患者在癌症扩散后被诊断出来。 PDAC被认为是 来自两种类型的非侵入性癌性病变，即胰腺上皮内肿瘤（Panins）， 以及在胰腺导管上皮中发展的导管内乳头肿瘤（IPMN）。 在这里，IPMN是大型囊性肿瘤，通过越来越多的频率检测到 腹部成像。全面的基因组分析表明，激活KRAS，GNA和 PI3KCA与IPMN发病机理有关。虽然基因工程的鼠标模型（GEMM） 已经为IPMN的发展提供了一些见解，在人类中如何在人类中出现IPMN 在IPMN病变（GNA和PIK3CA）中仅发现的突变以及合作事件促进的突变 尚不清楚向癌的发展。为了解决这个问题，我们开发了一个强大的平台 从人类胚胎干细胞（HESC）衍生的胰腺祖细胞中产生导管和acini器官。 使用人类外分泌胰腺，我发现GNASR201C在人体导管器官中的表达 概括了IPMN的几个特征，包括腔膨胀，以及粘蛋白（例如MUC2）的分泌。这 研究旨在检验以下假设：致癌GNA通过PKA独立促进细胞增殖 导管细胞中的机制，并与其他遗传事件合作，以促进起始和进展 IPMN病变在体内。结合细胞生物学，蛋白质组学和原位移植方法， 该建议旨在确定致癌GNA差异调节细胞的机制 导管和ACINI胰腺癌的增殖（AIM1）；并探索其他遗传事件 致癌GNA促进了在生理上的IPMN和IPMN衍生的PDAC的形成 准确的组织环境（AIM 2和3）。预期的结果将为原始单元的见解 IPMN病变；确定GNA促进早期病变的机制；并建立IPMN-的模型 派生的PDAC，可以长期使用治疗方法来治疗多种IPMN相关的PDAC 肿瘤。 K22奖将允许参加实验室管理，指导和赠款写作 讲习班和教学课程的入学，这将为我提供必要的知识，资源 并培训（a）了解OMICS研究原理； （b）小鼠模型癌； （c）申请额外 资金（R01）机会。在我的合作者的支持下以及建立咨询 委员会获得教师职位后，我的整体研究，培训和职业发展将帮助我 作为独立研究者建立胰腺癌研究的独特利基。