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）是一种致命的疾病，其生存率很低，仅为10%， 因为大多数病人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 由两种类型的非侵入性癌前病变引起，即胰腺上皮内瘤变（PanIN）， 以及在胰腺的导管上皮中发展的导管内乳头状粘液性肿瘤（IPMN）。 在这里，IPMN是大的囊性肿瘤，偶然发现的频率增加，通过 腹部成像全面的基因组分析表明，KRAS、GNAS和 PI 3 KCA与IPMN的发病有关。虽然基因工程小鼠模型（GEMM） 已经提供了一些见解IPMN的发展，如何IPMN出现在人类的背景下， 仅在IPMN病变中发现的突变（GNAS和PIK 3CA）以及协同事件促进的突变 发展为癌尚不清楚。为了解决这个问题，我们开发了一个强大的平台， 从人胚胎干细胞（hESC）衍生的胰腺祖细胞产生导管和腺泡类器官。 使用人胰腺外分泌，我发现GNASR 201 C在人导管类器官中的表达 概括了IPMN的几个特征，包括管腔扩张和粘蛋白如MUC 2的分泌。这 一项研究开始验证致癌GNAS通过PKA非依赖性促进细胞增殖的假设。 在导管细胞的机制，并与其他遗传事件合作，以促进启动和发展， 体内IPMN病变。使用细胞生物学、蛋白质组学和原位移植方法的组合， 这项建议旨在确定致癌GNAS差异调节细胞的机制， 导管和腺泡胰腺类器官（Aim 1）的增殖;并探索其他遗传事件， 致癌GNAS在生理学上可促进IPMN和IPMN衍生的PDAC的形成。 准确的组织环境（目标2和3）。预期的结果将提供对细胞起源的见解， IPMN损伤;确定GNAS促进早期损伤的机制;建立IPMN模型- 衍生的PDAC，其可以在治疗上长期用于治疗广泛的IPMN相关的 肿瘤的K22奖将允许参与实验室管理，指导和赠款写作 讲习班，并在教学课程注册，这将为我提供必要的知识，资源， 和培训，以（a）理解组学研究的原则;（B）在小鼠中建立癌症模型;以及（c）申请额外的 投资机会（R 01）。在我的合作者的支持下， 在获得教师职位后，我的整体研究，培训和职业发展将有助于我 作为独立研究者在胰腺癌研究中建立独特的利基。