Abstract B003: Pancreatic cancer cells activate arginine biosynthesis to adapt to myeloid-driven amino acid stress in the tumor microenvironment

Abstract

Abstract Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs to maintain survival and proliferation. Therefore, knowledge of microenvironmental nutrient levels and how cancer cells cope with such nutrition is critical to understand the metabolism underpinning cancer cell biology. Previously, we performed quantitative metabolomics of the interstitial fluid (the local perfusate) of pancreatic ductal adenocarcinoma (PDAC) tumors to comprehensively characterize nutrient availability in the microenvironment of these tumors. We have used this information to develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling study of PDAC metabolism under physiological nutrition. By transcriptomic analysis, we show that PDAC cells cultured in TIFM, compared to standard culture models, adopt a cellular state more similar to PDAC cells in tumors. Using the TIFM model, we then identified arginine biosynthesis as a critical metabolic adaptation PDAC cells engage to cope with microenvironmental nutrition. We further find that arginine biosynthesis enables PDAC cells to cope with microenvironmental arginine starvation, which we show is driven by myeloid cells in PDAC tumors. Altogether, these data show that nutrient availability in the microenvironment is an important determinant of PDAC metabolism and behavior, and models incorporating tumor nutrition enable detailed and mechanistic study of microenvironmentally-programmed PDAC cell states and phenotypes. Further, through use of the TIFM model, we identified both myeloid-driven arginine starvation as a major metabolic stress prevalent in the PDAC microenvironment, and the metabolic adaptations PDAC cells use to counter this nutritional challenge. Citation Format: Juan J. Apiz Saab, Lindsey N. Dzierozynski, Patrick B. Jonker, Zhou Zhu, Riona N. Chen, Moses Oh, Colin Sheehan, Kay F. Macleod, Christopher R. Weber, Alexander Muir. Pancreatic cancer cells activate arginine biosynthesis to adapt to myeloid-driven amino acid stress in the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B003.