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

2022; Cell Press; Volume: 34; Issue: 1 Linguagem: Inglês

10.1016/j.cmet.2021.12.001

1932-7420

Pravat Kumar Parida, Mauricio Marquez-Palencia, Vidhya R. Nair, Akash Kaushik, Kangsan Kim, Jessica Sudderth, Eduardo Quesada-Diaz, Ámbar Cajigas, Vamsidhara Vemireddy, Paula I. González-Ericsson, Melinda E. Sanders, Bret C. Mobley, Kenneth E. Huffman, Sunati Sahoo, Prasanna Alluri, Cheryl Lewis, Yan Peng, Robert Bachoo, Carlos L. Arteaga, Ariella B. Hanker, Ralph J. DeBerardinis, Srinivas Malladi,

Lung Cancer Research Studies

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.