Fatty acid synthesis is required for breast cancer brain metastasis

Gino B. Ferraro, Ahmed Ali, Alba Luengo, David P. Kodack, Amy Deik, Keene L. Abbott, Divya Bezwada, Landry Blanc, Brendan Prideaux, Xin Jin, Jessica M. Possada, Jiang Chen, Christopher R. Chin, Zohreh Amoozgar, Raphael Ferreira, Ivy X. Chen, Kamila Naxerova, Christopher Ng, Anna M. Westermark, Mark DuquetteSylvie Roberge, Neal I. Lindeman, Costas A. Lyssiotis, Jens Nielsen, David E. Housman, Dan G. Duda, Elena Brachtel, Todd R. Golub, Lewis C. Cantley, John M. Asara, Shawn M. Davidson, Dai Fukumura, Véronique A. Dartois, Clary B. Clish, Rakesh K. Jain, Matthew G. Vander Heiden

Research output: Contribution to journalArticlepeer-review

Abstract

Brain metastases are refractory to therapies that control systemic disease in patients with human epidermal growth factor receptor 2-positive breast cancer and the brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for brain metastatic breast cancer growth may introduce liabilities that can be exploited for therapy. Here we assessed how metabolism differs between breast tumors in brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in the brain. We determine that this phenotype is an adaptation to decreased lipid availability in the brain relative to other tissues, resulting in site-specific dependency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase reduces human epidermal growth factor receptor 2-positive breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies.

Original languageEnglish (US)
Pages (from-to)414-428
Number of pages15
JournalNature Cancer
Volume2
Issue number4
DOIs
StatePublished - Apr 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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