Metabolic diversity within breast cancer brain-tropic cells determines metastatic fitness

HER2+ breast cancer patients are presented with either synchronous (S-BM), latent (Lat), or metachronous (M-BM) brain metastases. However, the basis for disparate metastatic fitness among disseminated tumor cells of similar oncotype within a distal organ remains unknown. Here, employing brain metastatic models, we show that metabolic diversity and plasticity within brain-tropic cells determine metastatic fitness. Lactate secreted by aggressive metastatic cells or lactate supplementation to mice bearing Lat cells limits innate immunosurveillance and triggers overt metastasis. Attenuating lactate metabolism in S-BM impedes metastasis, while M-BM adapt and survive as residual disease. In contrast to S-BM, Lat and M-BM survive in equilibrium with innate immunosurveillance, oxidize glutamine, and maintain cellular redox homeostasis through the anionic amino acid transporter xCT. Moreover, xCT expression is significantly higher in matched M-BM brain metastatic samples compared to primary tumors from HER2+ breast cancer patients. Inhibiting xCT function attenuates residual disease and recurrence in these preclinical models.

Automated summary

Metabolic diversity and plasticity within brain-tropic cells play a crucial role in determining the metastatic fitness of HER2+ breast cancer patients. Lactate secretion by aggressive metastatic cells or lactate supplementation inhibits innate immunosurveillance and promotes overt metastasis. Inhibiting lactate metabolism can impede brain metastasis, but some brain metastatic cells adapt and survive through specific metabolic pathways. xCT, an amino acid transporter, is significantly upregulated in brain metastatic cells compared to primary tumors, and targeting xCT can attenuate residual disease and recurrence.