Abstract P1-06-08: Metabolic diversity determines metastatic fitness of breast cancer brain-tropic cells

Abstract

Abstract HER2+ breast cancer patients presenting with either synchronous (S-BM), latent residual (Lat) or metachronous (M-BM) brain metastases have poor survival outcomes. However, the basis for disparate metastatic fitness among disseminated tumor cells of similar oncotype within a distal organ remains unknown. Employing isogenic HER2+ breast cancer brain metastasis models, we show metabolic diversity and plasticity within brain-tropic cells determines metastatic fitness. Lactate secreted by aggressive metastatic cells (S-BM and M-BM) or lactate supplementation to mice bearing latent residual disease limits innate immune surveillance and triggers overt metastasis. Attenuating lactate metabolism in S-BM impedes metastasis, while M-BM adapt and survive as latent residual disease. In contrast to S-BM, Lat and M-BM survive in equilibrium with innate immune surveillance, oxidize glutamine and maintain cellular redox homeostasis through the anionic amino acid transporter xCT. Moreover, xCT expression is significantly higher in matched metachronous brain metastatic samples compared to primary tumors from HER2+ breast cancer patients. Genetic or pharmacological blockade of xCT eradicates residual disease and brain metastatic relapse in these preclinical models. Citation Format: Srinivas Malladi. Metabolic diversity determines metastatic fitness of breast cancer brain-tropic cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-06-08.