PDK1-Dependent Metabolic Reprogramming Dictates Metastatic Potential in Breast Cancer

Fanny Dupuy, Sébastien Tabariès, Sylvia Andrzejewski, Zhifeng Dong, Julianna Blagih, Matthew G Annis, Atilla Omeroglu, Dongxia Gao, Samuel Leung, Eitan Amir, Mark Clemons, Adriana Aguilar-Mahecha, Mark Basik, Emma E Vincent, Julie St-Pierre, Russell G Jones, Peter M Siegel

Research output: Contribution to journalArticle (Academic Journal)peer-review

274 Citations (Scopus)

Abstract

Metabolic reprogramming is a hallmark of cellular transformation, yet little is known about metabolic changes that accompany tumor metastasis. Here we show that primary breast cancer cells display extensive metabolic heterogeneity and engage distinct metabolic programs depending on their site of metastasis. Liver-metastatic breast cancer cells exhibit a unique metabolic program compared to bone- or lung-metastatic cells, characterized by increased conversion of glucose-derived pyruvate into lactate and a concomitant reduction in mitochondrial metabolism. Liver-metastatic cells displayed increased HIF-1α activity and expression of the HIF-1α target Pyruvate dehydrogenase kinase-1 (PDK1). Silencing HIF-1α reversed the glycolytic phenotype of liver-metastatic cells, while PDK1 was specifically required for metabolic adaptation to nutrient limitation and hypoxia. Finally, we demonstrate that PDK1 is required for efficient liver metastasis, and its expression is elevated in liver metastases from breast cancer patients. Our data implicate PDK1 as a key regulator of metabolism and metastatic potential in breast cancer.

Original languageEnglish
Pages (from-to)577-89
Number of pages13
JournalCell Metabolism
Volume22
Issue number4
DOIs
Publication statusPublished - 6 Oct 2015

Keywords

  • Animals
  • Breast Neoplasms
  • Carbon Isotopes
  • Cell Hypoxia
  • Cell Line, Tumor
  • Female
  • Gas Chromatography-Mass Spectrometry
  • Glutamine
  • Glycolysis
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Liver Neoplasms
  • Metabolic Engineering
  • Metabolome
  • Mice
  • Mice, Inbred BALB C
  • Oxidative Phosphorylation
  • Protein-Serine-Threonine Kinases
  • RNA Interference
  • RNA, Small Interfering
  • Journal Article
  • Research Support, Non-U.S. Gov't

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