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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a five-year survival rate ~10%1. PDAC is characterized by an altered/abnormal nutrient tumormicroenvironment (TME)2, and cancer cells must adapt metabolically, which exposes potentialtherapeutic targetable vulnerabilities. Therefore, we seek to identify metabolic pathways thatallow PDAC adaptation to such abnormal TME. The integrated stress response (ISR) is anintracellular stress response pathway that senses diverse stressors, and subsequently initiatesdownstream stress adaptations3. We find both murine and human PDAC have elevatedexpression of ATF4, the most well-characterized ISR effector, compared to paired healthypancreas by immunohistochemistry staining. Further, I find the ISR is activated and critical forPDAC survival/proliferation upon physiological PDAC TME nutrient stress. What is triggering theISR activation in PDAC? Through a variety of studies, I determined that it was the amino acidstress, specifically the depletion of arginine and asparagine, that activated the ISR upstreamkinase GCN2, which is responsible for ATF4 upregulation upon PDAC TME nutritional stress.Through CRISPR-based competition assays, I determined that ATF4 activity was critical forPDAC cells to cope with the depletion of arginine and asparagine, and ATF4 activity wasdispensable when these two amino acids were supplied even though cultured in PDACphysiological TME conditions. Currently, I am seeking to validate these findings in murine PDACmodels, and to determine if ATF4 or GCN2 could be relevant therapeutic targets, using an invivo tumor competition assay that I am developing. Altogether, I find the ISR is active in PDACboth ex vivo and in vivo, and suggest that the ISR is critical for PDAC survival/proliferation byallowing adaptation to abnormal PDAC amino acid TME. This work suggests that the ISR is anovel therapeutic target for PDAC treatment, which ultimately can benefit PDAC patients. References: 1. Cancer Facts & Figures 2021. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2021.html. 2. Sullivan, M. R. et al. Quantification of microenvironmental metabolites in murine cancersreveals determinants of tumor nutrient availability. Elife 8, (2019).3. Pakos-Zebrucka, K. et al. The integrated stress response. EMBO Rep. 17, 1374-1395(2016). Citation Format: Chufan Cai. The role of the integrated stress response in pancreatic cancer adaptation to tumor microenvironmental nutrient stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6197. |
