title: PDK1-Dependent Metabolic Reprogramming Dictates Metastatic Potential in Breast Cancer.
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.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Fanny
authors.initials: F
authors.lastname: Dupuy
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Tabariès
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Andrzejewski
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Julianna
authors.initials: J
authors.lastname: Blagih
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Annis
authors.affiliation: Department of Pathology, McGill University Health Center, Montréal, QC H4A 3J1, Canada.
authors.forename: Atilla
authors.initials: A
authors.lastname: Omeroglu
authors.affiliation: Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Dongxia
authors.initials: D
authors.lastname: Gao
authors.affiliation: Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Leung
authors.affiliation: Department of Medicine, University of Toronto, Toronto, ON M5G 2M9, Canada.
authors.forename: Eitan
authors.initials: E
authors.lastname: Amir
authors.affiliation: Division of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON K1H 8L6, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Clemons
authors.affiliation: Segal Cancer Centre, Sir Mortimer B. Davis Jewish General Hospital, Montréal, QC H3T 1E2, Canada.
authors.forename: Adriana
authors.initials: A
authors.lastname: Aguilar-Mahecha
authors.affiliation: Segal Cancer Centre, Sir Mortimer B. Davis Jewish General Hospital, Montréal, QC H3T 1E2, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Basik
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Vincent
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: St-Pierre
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montréal, QC H3A 1A3, Canada. Electronic address: russell.jones@mcgill.ca.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Jones
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, QC H3A 1A3, Canada. Electronic address: peter.siegel@mcgill.ca.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siegel
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002247:Carbon Isotopes / Q000737:chemistry / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D060847:Metabolic Engineering; D055442:Metabolome; D051379:Mice; D008807:Mice, Inbred BALB C; D010085:Oxidative Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D002247:Carbon Isotopes; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034741:RNA, Small Interfering; D005973:Glutamine; D017346:Protein Serine-Threonine Kinases