Metabolic Adaptations Alter Metastatic Fitness in Brain-Tropic Breast Cancer

Human epidermal growth factor receptor 2 (HER2)–amplified breast cancer has a high incidence of brain metastasis, but the fitness of these disseminated tumor cells to the brain and the role metabolism has in this process remain to be fully elucidated. Furthermore, the adaptations that support differences between synchronous, metachronous, or residual brain metastasis also have not been completely defined. Parida and colleagues used a phenotypic screen in mice to isolate synchronous (S-BM, metastasis along with the primary tumor), latent residual (Lat), or metachronous (M-BM, delayed metastatic relapses that arise from latent residual cells) brain metastases to determine metabolic adaptations and vulnerabilities in these populations. These different metastatic states were metabolically distinct, with levels of secreted lactate being higher in aggressive S-BM and M-BM, while glutamate secretion was elevated in Lat and M-BM cells. Lactate supplementation promoted escape from natural killer (NK)–cell surveillance through reduction in NK-cell cluster size, number, and cytotoxic enzymes thereby increasing metastatic incidence. Use of sodium oxamate, an analog of pyruvate that blocks the pyruvate to lactate conversion, led to a significant decrease in metastasis only in S-BM cells, and genetic inhibition of lactate dehydrogenase A, the enzyme that catalyzes the conversion of pyruvate to lactate, reduced S-BM oncosphere formation and metastatic occurrence relative to M-BM. Moreover, M-BM cells demonstrated low reactive oxygen species (ROS) and a high reduced glutathione/oxidized glutathione ratio relative to S-BM, suggesting M-BM cells are more efficient at redox modulation that promotes their survival. Subunits of the xCT cystine/glutamate antiporter were also enriched in Lat and M-BM cells, and pharmacologic or genetic inhibition of xCT increased ROS levels as well as a reduced cell viability and metastatic incidence in Lat and M-BM cells. Dual treatment of cells with an xCT inhibitor and a HER2 tyrosine kinase inhibitor showed benefit only in M-BM cells. This study indicates that metastatic fitness can be influenced by metabolic diversity in brain-tropic HER2⁺ breast cancer cells and suggests that precise targeting of the differences between these metastatic types can improve disease-free survival.

Parida PK, Marquez-Palencia M, Nair V, Kaushik AK, Kim K, Sudderth J, et al. Metabolic diversity within breast cancer brain-tropic cells determines metastatic fitness. Cell Metab 2022;34:90–105.e7.

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