Adult pancreatic centroacinar cells as cells of origin of PDAC and the key role of a metabolic regulator in the transformation process

• Applicant: Professor Anthony Gavalas, Ph.D.
• Subject Area: Gastroenterology ; Hematology, Oncology ; Cell Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 575882142

Pancreatic ductal adenocarcinoma (PDAC) represents over 90% of pancreatic cancer cases and it is among the most lethal forms of cancer, also because it is often diagnosed at an advanced stage due to its asymptomatic nature and the lack of early molecular markers. Activating Kras mutations (Kras*) are the initiating event in more than 90% of PDAC cases and are required for tumor maintenance. Recent advances in pharmacologically targeting Kras offer renewed hope, but combinatorial treatments would likely provide even better prospects. The cells of origin of PDAC remain unknown, which hinders efforts to identify early molecular markers of the disease and understand the core molecular machinery of the transformed, dividing cells. Effective targeting of this machinery will help treat the disease and limit the possibility of relapse. We propose that strong candidate cells of origin would be adult, mitotically active, progenitor cells, which already express Kras. Previous work in our lab showed that Aldh1b1-expressing centroacinar cells (CACs) fulfill these criteria. Additionally, we found that a functional Aldh1b1 is necessary in a PDAC mouse model for the development of the disease. To evaluate whether PDAC may originate from these cells and elucidate the implication of Aldh1b1 function, we have generated and validated several new mouse lines. Preliminary experiments suggest that the targeted expression of Kras* in Aldh1b1+ CACs results in neoplasias and that isolated, expanded in vitro, Kras* / Aldh1b1 expressing CACs give rise to neoplasias after orthotopic transplantation in Nu/Nu mice. In this grant application, we propose to quantitatively evaluate the potency of these cells in giving rise to neoplasias and eventually PDAC, using targeted expression of Kras* in CACs in the absence and presence of pancreatitis as well as transplantation of in vitro expanded CACs. To assess the cell autonomous requirement of Aldh1b1 in PDAC initiation, we will eliminate Aldh1b1 while inducing Kras* expression in the CACs. Mechanistically, we will determine the early metabolic effects, including levels of reactive oxygen species (ROS), of Kras* expression in the CACs and ask to what extent Aldh1b1 mediates the Kras* dependent metabolic reprogramming and mitigates ROS levels to allow the expansion of the Kras* transformed cells and PDAC development. Finally, we will analyze the early effects of Kras* expression in the transcriptome and the epigenome of the CACs and evaluate the implication of Aldh1b1 in gene expression and chromatin regulation. Our animal models will allow us to investigate the early effects of Kras* in adult pancreas progenitors, something that, to our knowledge, has not been possible so far. The combination of these experiments will identify regulatory networks that would be potential targets for PDAC therapies.

• DFG Programme: Research Grants