Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.

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ICR Authors

Bruna Cabot, Alejandra
 Poulogiannis, Georgios

Authors

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

Document Type

Journal Article

Date

2023-11-01

Date Accepted

2023-09-28

Abstract

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.

Citation

Nature Metabolism, 2023, 5 (11), pp. 1870 - 1886

DOI

10.1038/s42255-023-00915-7
10.1038/s42255-023-00915-7

URI

https://repository.icr.ac.uk/handle/internal/6138

Rights

http://creativecommons.org/licenses/by/4.0/

Source Title

Nature Metabolism

Publisher

NATURE PORTFOLIO

ISSN

2522-5812

eISSN

2522-5812
2522-5812

Collections

Cell and Molecular Biology

Research Team

Preclin Paed Cancer Evo
Signalling Cancer Metab

Notes