Telomerase in regeneration and cancer of the pancreas

• Applicant: Dr. Patrick Neuhöfer
• Subject Area: Gastroenterology ; Evolutionary Cell and Developmental Biology (Zoology)
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 264550824

The pancreas contains two functional and histomorphological compartments, the endocrine and exocrine pancreas. The endocrine pancreas is responsible for regulating glucose homeostasis. The primary role of the exocrine pancreas is the production of enzymes for nutrient digestion. The biology of the pancreas has been studied intensively to improve treatment options for devastating pancreatic diseases, such as pancreatitis, pancreatic ductal adenocarcinoma (PDAC) and diabetes. Recent advances in stem cell biology increased interest in the events in cell fate decisions during embryonic development and regeneration of the pancreas.The enzyme telomerase consists of the reverse transcriptase TERT and the RNA template TERC. Telomerase has emerged as a critical stem cell factor, active in embryonic cells during development, but also in stem and progenitor cells in the adult organism. The canonical function of telomerase is to add telomere repeats to chromosome ends, thereby preventing the consequent induction of replicative senescence or apoptosis. This canonical function of telomerase requires both TERT and TERC. However, there is growing evidence that TERT has other (non-canonical) functions, e.g. a role in stem cell function and tissue homeostasis. In the first part of this proposal I am planning to investigate the role of TERT in pancreatic development and regeneration. To discover new stem cell populations in the pancreas, I will use a novel TERT-GFP knock-in reporter mouse strain, recently generated in the Artandi laboratory, to analyze the expression patterns of TERT at different time points during pancreatic development. FACS analysis of TERT+ cells will show if TERT marks pancreatic stem/progenitor cells. I will analyze the role of TERT in exocrine regeneration by inducing pancreatitis in a second knock-in strain, a TERT- inducible Cre recombinase reporter mouse line, and perform lineage-tracing studies to scrutinize if TERT+ cells are involved in exocrine regeneration. I will also evaluate the function of non-canonical telomerase by pancreas-specific inactivation of TERT during acute pancreatitis.Pancreatic cancer is the fourth leading cause for cancer-related deaths with the lowest 5-year survival rate of any cancers. Telomerase is reactivated in 90% of human cancers via transcriptional upregulation of TERT and variants in the TERT gene predispose to pancreatic cancer in humans. In the second part of this proposal I will analyze the expression patterns of TERT in a Kras-induced mouse model of PDAC and isolate TERT+ cells to see if TERT is a marker for pancreatic cancer stem cells. Additionally, I will investigate the non-canonical functions of TERT in this PDAC model. Taken together, these experiments will yield new insights into stem cell function in pancreatic development and pancreatic regeneration, while revealing how early pancreatic cancers cells circumvent senescence barriers to become fully malignant.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Steven Artandi, Ph.D.