Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation.
Date
2019-06-20Author
van Weverwijk, A
Koundouros, N
Iravani, M
Ashenden, M
Gao, Q
Poulogiannis, G
Jungwirth, U
Isacke, CM
Type
Journal Article
Metadata
Show full item recordAbstract
The different stages of the metastatic cascade present distinct metabolic challenges to tumour cells and an altered tumour metabolism associated with successful metastatic colonisation provides a therapeutic vulnerability in disseminated disease. We identify the aldo-keto reductase AKR1B10 as a metastasis enhancer that has little impact on primary tumour growth or dissemination but promotes effective tumour growth in secondary sites and, in human disease, is associated with an increased risk of distant metastatic relapse. AKR1B10High tumour cells have reduced glycolytic capacity and dependency on glucose as fuel source but increased utilisation of fatty acid oxidation. Conversely, in both 3D tumour spheroid assays and in vivo metastasis assays, inhibition of fatty acid oxidation blocks AKR1B10High-enhanced metastatic colonisation with no impact on AKR1B10Low cells. Finally, mechanistic analysis supports a model in which AKR1B10 serves to limit the toxic side effects of oxidative stress thereby sustaining fatty acid oxidation in metabolically challenging metastatic environments.
Collections
Subject
Cell Line, Tumor
Spheroids, Cellular
Animals
Humans
Mice
Breast Neoplasms
Lung Neoplasms
Neoplasm Recurrence, Local
Aldehyde Reductase
Fatty Acids
Xenograft Model Antitumor Assays
Oxidation-Reduction
Glycolysis
Oxidative Stress
Female
HEK293 Cells
Aldo-Keto Reductases
Research team
Molecular Cell Biology
Signalling & Cancer Metabolism
Language
eng
Date accepted
2019-05-16
License start date
2019-06-20
Citation
Nature communications, 2019, 10 (1), pp. 2698 - ?
Publisher
NATURE PUBLISHING GROUP