Epigenetic and transcriptional alterations in pancreatic cancer - influence on molecular subtypes, chemosensitivity, and metastatic potential

• Applicant: Dr. Andreas Carl-Stephan Leonhardt
• Subject Area: General and Visceral Surgery
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 423165260

Despite significant progress in medical and surgical treatment of pancreatic ductal adenocarcinoma (PDAC), the prognosis remains dim. Recent research could identify two distinct subtypes of pancreatic cancer based on transcriptomic data: the basal-like subtype is associated with resistance against common chemotherapeutic regimens and dismal prognosis while the classical subtype is chemotherapy sensitive and associated with a better prognosis. Preliminary data point towards the importance of epigenetic and transcriptional alterations in determining subtype and therefore chemotherapeutic sensitivity. We hypothesize that by identifying and targeting candidate genes and hence epigenetic as well as transcriptional dependencies a shift from the basal-like to the classical subtype can be induced. We aim to test this hypothesis as follows: 1.) Using pancreatic cancer derived organoids (PDO) in a CRISPR/Cas9 genetic screen, we aim to systematically identify candidate genes and associated epigenetic and transcriptional dependencies. GATA6 expression has been reported to serve as robust surrogate marker for the classical subtype. Basal-like PDOs expressing GFP under the control of the GATA6 promoter will be engineered and utilized for the screen. Increase of green fluorescence will indicate a shift towards the classical subtype. 2.) Candidate genes will then be characterized on a transcriptomic as well as epigenetic level. 3.) Available small molecule inhibitors will be used as single agents as well as in rationally designed combinations based on identified alterations. In vivo confirmation of candidate genes as well as their pharmacological modulation will be performed by orthotopically transplanting PDOs into standard mouse models. Using these models, effects on tumor growth and metastases after modification of subtype can be directly assessed. 4.) To investigate the stability of subtypes during the metastatic process, samples of primary tumors and matched synchronous as well as metachronous metastases will be profiled using described transcriptomic signatures. Additionally, epigenetic and transcriptomic marks will be tested based on identified candidate genes. Collectively, this project is designed to contribute to pancreatic cancer research through a better understanding of the clinical importance of epigenetic and transcriptional alterations in PDAC and as such as, improve patient survival suffering from this devastating disease.

• DFG Programme: Research Fellowships
• International Connection: USA
• Hosts: Professor Dr. Markus W. Büchler; Professor Dr. Rienk Offringa; Professor Dr. Oliver Strobel; Professor David A. Tuveson, Ph.D., until 11/2019; Professor Richard White, Ph.D., since 11/2019