Metabolic and mitochondrial heterogeneity in pancreatic ductal adenocarcinoma - impact on therapy and resistance mechanisms

• Applicants: Dr. Theodore Alexandrov, since 1/2021; Professor Dr. Jens T. Siveke
• Subject Area: Gastroenterology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421166016

Pancreatic ductal adenocarcinoma (PDAC) is the solid cancer with the worst prognosis and largely due to a high intrinsic therapy resistance. An ongoing unresolved issue is the inter- and intratumoral heterogeneity of the PDAC tumors. While genetic heterogeneity exists beyond homogeneous alterations in KRAS, TP53 and CDKN2a, there is almost no insights into the phenotypic heterogeneity. Investigations are hampered by a very difficult access to the tissue and high desmoplastic stroma, which makes analyses of primary tumor cells nearly impossible. Thus, little is known about a metabolic heterogeneity of tumor cell subpopulations and how they are influencing chemotherapy response or resistance. A study in esophageal adenocarcinoma demonstrated that preexisting defects in the mitochondrial respiratory chain significantly influence response/resistance against platin-based chemotherapy. We thus hypothesize that mitochondria and the cellular metabolism are critical factors for response or resistance against chemotherapies. In preliminary work, we provide evidence in human as well as in murine tumors that PDAC shows metabolic and mitochondrial heterogeneity. Those findings shall be further investigated in this proposal. The difficulties of tissue accessibility in PDAC shall be overcome by applying high resolution imaging mass spectrometry (MALDI-FT-ICR), a method allowing mass spectrometric metabolomic analyses directly in conventional histological sections. This project will have a focus on metabolomic investigations in patient tissues and a genetically engineered PDAC mouse model to investigate cell and compartment-specific spatial organisation of metabolic processes in PDAC. Additionally, a large number of functional analyses in cell lines is planned. To the background that until now there is only a little knowledge about inter- and intratumoral heterogeneity in PDAC, our first aim is the systematic characterization of metabolic and mitochondrial heterogeneity in PDAC in human as well as in murine tumors. Further, we aim to investigate the influence of the cell metabolism and its heterogeneity for response and resistance mechanisms against chemotherapies (gemcitabine, paclitaxel, 5-FU, oxaliplatin). The third aim will be to validate metabolomic/mitochondrial molecules as new therapeutic targets. The overall goal of this proposal is to generate a new basis of knowledge about the phenotypic metabolomic and mitochondrial heterogeneity and their influence on response/resistance mechanisms. New therapeutic target structures should be defined and validated for improved therapeutic strategies to increase therapy response or block resistance in PDAC.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Dr. Michaela Aichler, until 1/2021