Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.
Date
2023-11-01Author
Kreuzaler, P
Inglese, P
Ghanate, A
Gjelaj, E
Wu, V
Panina, Y
Mendez-Lucas, A
MacLachlan, C
Patani, N
Hubert, CB
Huang, H
Greenidge, G
Rueda, OM
Taylor, AJ
Karali, E
Kazanc, E
Spicer, A
Dexter, A
Lin, W
Thompson, D
Silva Dos Santos, M
Calvani, E
Legrave, N
Ellis, JK
Greenwood, W
Green, M
Nye, E
Still, E
CRUK Rosetta Grand Challenge Consortium
Barry, S
Goodwin, RJA
Bruna, A
Caldas, C
MacRae, J
de Carvalho, LPS
Poulogiannis, G
McMahon, G
Takats, Z
Bunch, J
Yuneva, M
Type
Journal Article
Metadata
Show full item recordAbstract
Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy1-3. Consequently, spatially resolved omics-level analyses are gaining traction4-9. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism10,11. Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B5) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets.
Collections
Subject
Humans
Mice
Animals
Female
Breast Neoplasms
Pantothenic Acid
Proto-Oncogene Proteins c-myc
Transcription Factors
Vitamins
Research team
Preclin Paed Cancer Evo
Signalling Cancer Metab
Language
eng
Date accepted
2023-09-28
License start date
2023-11-01
Citation
Nature Metabolism, 2023, 5 (11), pp. 1870 - 1886
Publisher
NATURE PORTFOLIO