Abstract
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.
Original language | English (US) |
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Pages (from-to) | 90-105.e7 |
Journal | Cell Metabolism |
Volume | 34 |
Issue number | 1 |
DOIs | |
State | Published - Jan 4 2022 |
Keywords
- HER2
- breast cancer brain metastasis
- immune surveillance
- late recurrences
- metabolism
- metastasis
- metastatic dormancy
- metastatic latency
- redox homeostasis
- relapse
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology