Kras-Induced Cellular Plasticity in Pancreatic Cancer

Kras 诱导的胰腺癌细胞可塑性

基本信息

批准号：
9275927
负责人：
STEPHEN F KONIECZNY
金额：
$ 31.24万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9275927
关键词：
Acinar Cell Address Adenocarcinoma Cell Affect Automobile Driving Biological Biological Markers Biology Cancer Etiology Cancer Patient Cancerous Cell physiology Cessation of life Communities Data Development Diagnostic Disease Duct (organ) structure Ductal Ductal Epithelial Cell Epithelial Cells Event Failure Fostering Foundations Future Gene Expression Gene Targeting Genes Genetic Genetic Transcription Goals Health Health Care Costs Histologic Human Image Investigation KRAS2 gene Knowledge Lead Lesion Malignant Neoplasms Malignant neoplasm of pancreas Metaplasia Metaplastic Metastatic to Mission Modeling Mus Mutation Neoplasm Metastasis Outcome Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pancreatic duct Pathway interactions Patient-Focused Outcomes Patients Phenotype Population Primary Neoplasm Process Proto-Oncogenes Public Health Research Sampling Survival Rate System Tamoxifen Testing Therapeutic TimeLine Treatment Efficacy Tumor stage advanced disease base care systems gain of function gene product genome-wide improved in vivo innovation loss of function mortality mouse model novel pancreatic neoplasm prevent programs public health relevance response three dimensional cell culture tool transcription factor transcriptome tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): The 5 year survival rate for patients with pancreatic ductal adenocarcinoma (PDAC) has improved only marginally (3% -> 6%) over the past 35 years and despite considerable effort to develop therapeutics to treat PDAC, there has been a failure to significantly shift patient outcome. What is required are new, innovative and complementary approaches that better define the biology that drives disease initiation and that sustains tumor formation and progression so that improved treatments can be developed. PDAC is thought to initiate in acinar cells that acquire an activating mutation in the Kras protooncogene and that subsequently transition to a duct- like state by a process known as acinar-ductal metaplasia (ADM). Although ADM is a common feature of pancreatic cancer patients, there remains a critical gap in defining the transcriptional networks that are triggered by Kras mutation and that control the ADM -> PDAC pathway. The long-term goals of this study are to define the biological pathways that initiate and maintain advanced disease. The objective is to identify the transcriptional changes that are induced upon Kras activation and to test their importance to tumor development. The central hypothesis is that PDAC initiates from acinar cells via a phenotypic switch that requires silencing the acinar transcription program and activating a ductal transcription program. This hypothesis will be tested by pursuing two Specific Aims - (1) to identify acinar transcription networks that prevent acinar -> PDAC progression and (2) to establish how the ductal SOX9 transcription network drives ADM/PDAC development. These complementary aims will be accomplished using gain-of-function and loss- of-function strategies in inducible PDAC mouse models and in 3D culture systems that mimic the in vivo ADM response. The central transcription events instrumental in KRAS-induced ADM will be rigorously tested in human PDAC cells and in primary patient samples. The rationale for the proposed research is that these studies will be the first to probe the initial transcriptional changes in KRAS-expressing acinar cells and the first to manipulate these pathways in PDAC tumors. This contribution is significant because it will (i) define the earliest regulatory points n KRAS-induced PDAC, (ii) identify downstream genes that are regulated by duct transcription networks, and (iii) test if perturbation of specific gene targets can influence tumor development. The proposed research is innovative because it represents a departure from the status quo by approaching the disease from the earliest transcriptional events that guide the conversion of acinar cells to ductal preneoplastic lesions and by following these transcriptional networks in pancreatic tumors. The discoveries made will define the primary biological events associated with PDAC (the fourth leading cause of cancer deaths in the U.S.) and will direct future approaches aimed at testing new biomarkers and developing improved diagnostic and therapeutic tools to successfully treat patients suffering from this deadly disease.

描述（由申请人提供）：在过去的35年中，胰腺导管腺癌（PDAC）的5年生存率仅在略有改善（3％ - > 6％）方面提高了，尽管开发了治疗PDAC治疗PDAC的大量努力，但仍未发生显着转移患者的结果。所需的是新的，创新的和互补的方法，可以更好地定义驱动疾病启动并维持肿瘤形成和进展的生物学，从而可以开发出改进的治疗方法。据认为，PDAC在腺泡细胞中启动，这些细胞在KRAS原子元中获得了激活突变，并通过称为腺泡 - 导管化学的过程（ADM）将其过渡到类似管状的状态（ADM）。尽管ADM是胰腺癌患者的共同特征，但定义由KRAS突变触发并控制ADM-> PDAC途径的转录网络仍然存在关键差距。这项研究的长期目标是定义启动和维持晚期疾病的生物学途径。目的是确定KRAS激活后引起的转录变化，并测试其对肿瘤发育的重要性。中心假设是PDAC通过表型开关从腺泡细胞启动，该开关需要使腺泡转录程序沉默并激活导管转录程序。该假设将通过追求两个具体目标来检验 - （1）确定可预防腺泡 - > PDAC进展的刺激转录网络，以及（2）确定导管SOX9转录网络如何驱动ADM/PDAC开发。这些补充目标将使用诱导性PDAC小鼠模型中的功能获得和功能损失策略以及模仿体内ADM响应的3D培养系统中实现。在人类PDAC细胞和主要的患者样品中，将在KRAS诱导的ADM中发挥作用的中心转录事件。拟议的研究的基本原理是，这些研究将是第一个探测表达KRAS腺泡细胞的初始转录变化的方法，也是第一个在PDAC肿瘤中操纵这些途径的研究。该贡献很重要，因为它将（i）定义最早的调节点N KRAS诱导的PDAC，（ii）识别受管道转录网络调节的下游基因，以及（iii）测试特定基因靶标是否会影响肿瘤的发展。拟议的研究具有创新性，因为它通过从最早的转录事件接近指导腺泡细胞转化为导管性肿瘤性病变的最早转录事件，并通过胰腺肿瘤中的这些转录网络遵循这些转录网络。提出的发现将定义与PDAC（美国癌症死亡的第四个主要原因）相关的主要生物事件，并将指导旨在测试新生物标志物并开发改进的诊断和治疗工具的未来方法，以成功治疗患有这种致命疾病的患者。