Abstract A039: Metabolic evolution in breast cancer predicts organ-specific metastasis

Abstract

Abstract The metastatic cascade is a critical component of cancer evolution. Understanding the rewired metabolism in organ-specific metastasis in breast cancer could help identify strategies to improve the treatment and prevention of metastatic disease. Here, we used a systems biology approach to assess the evolution of metabolic fluxes from parental breast cancer cells to their brain- and lung-homing metastatic derivatives. We found that divergent lineages had distinct, heritable metabolic fluxes. Lung-homing cells maintained adaptations for high glycolytic flux despite low levels of glycolytic intermediates, constitutively activating a pathway sink into lactate. This exacerbated Warburg effect –– stronger than the Warburg effect in the primary tumor –– was associated with a high ratio of lactate dehydrogenase (LDH) to pyruvate dehydrogenase (PDH) expression, a signature which correlated with lung metastasis in patients with breast cancer. While feature classification models trained on clinical characteristics alone were unable to predict tropism, the LDH/PDH ratio was a significant predictor of a patient's future metastasis to the lung but not to other organs, independent of other transcriptomic signatures. Lung- and brain-homing lineages had differential selection patterns in acidic metabolic microenvironments. High lactate efflux was also a trait in lung-homing metastatic pancreatic cancer cells, suggesting that lactate production may be a convergent phenotype in lung metastasis. Together, these analyses highlight the essential role that metabolic evolution plays in organ-specific cancer metastasis and identify a putative biomarker for predicting lung metastasis in breast cancer patients. Citation Format: Deepti Mathur, Chen Liao, Wendy Lin, Alessandro La Ferlita, Salvatore Alaimo, Samuel Taylor, Yi Zhong, Christine Iacobuzio-Donahue, Alfredo Ferro, Joao Xavier. Metabolic evolution in breast cancer predicts organ-specific metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A039.