Is ATM deficiency provide a benefit to pancreatic tumor cells in a metabolic stress context?

Despite decades of extensive basic and translational research improving our understanding of pancreatic ductal adenocarcinoma (PDAC) biology, PDAC is predicted to become the second-leading cause of cancer-related death in 2030. This dark prognostic is partly explained by the heterogeneous PDAC mutational landscape and an extensive ability to undergo cellular reprogramming, including metabolic switch. PDACs are characterized by a dense desmoplastic stroma, resulting in reduced blood perfusion and a subsequent nutrient-poor microenvironment. Numerous studies already highlight the correlation between tumoral mutational patterns and distinct metabolic reprogramming. We previously demonstrated that the loss of the DNA damage response ATM serine/threonine kinase is associated with an aggressive mesenchymal phenotype, including a dense and collapsed tumor stroma. In such a context, we suggest that ATM-deficient pancreatic cancer cells exhibit improved metabolic reprogramming ability, which in turn could support tumor progression. In order to decipher how ATM status might affect PDAC cell metabolic reprogramming, and because there is increasing evidence that disease progression of ATM-deficient PDAC depends on the mutational status of Trp53, we used ATM and/or P53-depleted cell lines established from our KC (LSL-Kras^G12D/+;Ptf1a^Cre/+ ), AKC (Atm^fl/fl; LSL-Kras^G12D/+; Ptf1a^Cre/+) KPC (LSL-Kras^G12D/+; Trp53^fl/fl; Ptf1a^Cre/+ ), and AKPC (Atm^fl/fl; LSL-Kras^G12D/+; Trp53^fl/fl; Ptf1a^Cre/+) mouse models. Initial data revealed that ATM loss correlates with a higher aerobic glycolysis metabolism (Warburg effect) compared to their ATM-proficient counterparts in both P53-depleted and non-depleted contexts. Interestingly, we also observe ATM-deficiency as associated with the overexpression of several genes involved in glycolysis, lactate synthesis, and branched-chain amino acid anabolism (e.g., Pgk1, Bcat1). Additionally, it appears that ATM-depleted PDAC cells have a greater ability to proliferate under nutrient-poor conditions, and maintain their migration features, unlike ATM-proficient cells. Overall, these preliminary data suggest that the loss of ATM in PDAC cells promotes metabolic reprogramming and thus confers survival and tumor plasticity advantages.

Publication History

Article published online:
07 September 2021