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

作者：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 · 发表于：Cell Metabolism · 年份：2022 · DOI：10.1016/j.cmet.2021.12.001 · 被引用次数：105 · 研究领域：Brain Metastases and Treatment、Glioma Diagnosis and Treatment、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.