Abstract B002: Lactate metabolism regulates chromatin accessibility and prostate luminal differentiation

Abstract Lineage transitions are a central feature of prostate development, tumorigenesis and treatment resistance. While epigenetic changes drive prostate lineage transitions, whether upstream metabolic signaling modulates prostate lineage identity remains unclear. Investigations into prostate metabolism are focused primarily on targeting energy metabolism without considering how altering metabolism may influence epigenetic state or cellular differentiation. To understand the relationship between metabolism and prostate lineage identity, we developed an approach to perform metabolic profiling and nutrient tracing on primary prostate epithelial cells and demonstrated that basal and luminal cells exhibit distinct metabolic features. Furthermore, we show that basal to luminal differentiation in vivo and in three-dimensional ex vivo culture is accompanied by metabolic changes consistent with increased glucose oxidation. Using genetic and pharmacological approaches, we identify the mitochondrial pyruvate carrier (MPC) as a regulator of prostate luminal identity in benign and prostate cancer cells. Low MPC expression is inversely correlated with luminal differentiation and associated with poor response to androgen receptor inhibition in clinical prostate cancer. Mechanistically, our results suggest that MPC inhibition likely impairs luminal differentiation through accumulation of intracellular lactate. Increasing intracellular lactate levels is sufficient to alter chromatin accessibility at lineage-specific genes and impair luminal differentiation in prostate epithelial cells. These findings indicate that upstream metabolism is a regulator of chromatin accessibility and prostate lineage differentiation, suggesting that alterations in tumor metabolism may contribute to lineage plasticity and resistance to androgen receptor blockade in prostate cancer. Citation Format: Andrew S. Goldstein, Jenna M. Giafaglione, Preston D. Crowell. Lactate metabolism regulates chromatin accessibility and prostate luminal differentiation [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B002.