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

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 languageEnglish (US)
Pages (from-to)90-105.e7
JournalCell Metabolism
Volume34
Issue number1
DOIs
StatePublished - 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

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