Functional in vivo characterisation of the role of epigenetic regulators for pancreatic cancer development and maintenance

表观遗传调节因子在胰腺癌发生和维持中的作用的功能性体内表征

• 批准号: 286466381
• 负责人: Professor Dr. Josef Leibold
• 金额: --
• 依托单位: Cancer Biology and Genetics (CBG) Program
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/286466381?language=en
• 关键词: Functional; vivo; characterisation; role; epigenetic

Pancreatic Ductal Adenocarcinoma (PDAC) represents a major health problem. It constitutes fourth leading cause of cancer death in the United States with a 5-year survival rate of only ~7 %, and the prognosis of patients suffering from PDAC has not significantly improved over the past 30 years. Radical surgery is a curative option, however, due to diagnosis in advanced stages, often not applicable. Systemic chemotherapy shows limited therapeutic efficacy, providing only modest gain in survival. Recent high throughput genetic analyses of patient derived PDAC samples revealed, besides well known driver lesions like Kras, p53, CDKN2A and Smad4, several new mutations as potential drivers of PDAC initiation and progression. Interestingly many of these mutations affect genes with established roles in epigenetic regulation like chromatin organization or histone modifications. Among these genes are components of the SWI/SNF chromatin remodelling complex (e.g. Arid1a/b and Smarca4), which were found frequently mutated and were hypothesized to represent tumor suppressor genes. Until now it is not yet fully understood how alterations in epigenetic regulators contribute to the development and maintenance of cancer. The first aim of this project is to investigate the role of the chromatin remodelling subunits Arid1a, Arid1b and Smarca4 in the development, maintenance and progression of PDAC. To address this question a newly developed embryonic stem cell based PDAC mouse model will be used and the role of the SWI/SNF subunits during tumor development will be genetically dissected using conditional RNA interference (RNAi). Furthermore, I will investigate, whether sustained loss of SWI/SNF factors is required for PDAC maintenance and whether the altered epigenetic landscape also plays a role in therapy resistance of PDACs. Finally, I aim to conduct negative selection pooled shRNA screens to identify synthetic lethalities specifically in such PDACs, which harbour alterations in SWI/SNF complex subunits.

胰腺导管腺癌（PDAC）是一个主要的健康问题。它是美国第四大癌症死亡原因，5年生存率仅为7%左右，并且PDAC患者的预后在过去30年里没有显着改善。根治性手术是一种治疗选择，但由于诊断已处于晚期，通常不适用。全身化疗的治疗效果有限，仅能适度提高生存率。最近对患者 PDAC 样本进行的高通量遗传分析显示，除了众所周知的驱动病变（如 Kras、p53、CDKN2A 和 Smad4）之外，还有一些新突变是 PDAC 启动和进展的潜在驱动因素。有趣的是，其中许多突变影响在表观遗传调控中具有既定作用的基因，例如染色质组织或组蛋白修饰。这些基因中包括 SWI/SNF 染色质重塑复合体的组成部分（例如 Arid1a/b 和 Smarca4），这些基因经常发生突变，并被假设为代表肿瘤抑制基因。到目前为止，尚未完全了解表观遗传调节因子的改变如何促进癌症的发展和维持。该项目的首要目标是研究染色质重塑亚基 Arid1a、Arid1b 和 Smarca4 在 PDAC 的发育、维持和进展中的作用。为了解决这个问题，将使用新开发的基于胚胎干细胞的 PDAC 小鼠模型，并使用条件 RNA 干扰 (RNAi) 对 SWI/SNF 亚基在肿瘤发育过程中的作用进行基因剖析。此外，我将研究 PDAC 的维持是否需要 SWI/SNF 因子的持续丧失，以及表观遗传景观的改变是否也在 PDAC 的治疗抵抗中发挥作用。最后，我的目标是进行负选择混合 shRNA 筛选，以识别此类 PDAC 中的合成致死率，这些 PDAC 包含 SWI/SNF 复合亚基的改变。