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

• Applicant: Professor Dr. Josef Leibold
• Subject Area: Gastroenterology
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 286466381

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.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Scott Lowe, Ph.D.