TY - JOUR
T1 - Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer
AU - Kreuzaler, Peter
AU - Inglese, Paolo
AU - Ghanate, Avinash
AU - Gjelaj, Ersa
AU - Wu, Vincen
AU - Panina, Yulia
AU - Mendez-Lucas, Andres
AU - MacLachlan, Catherine
AU - Patani, Neill
AU - Hubert, Catherine B.
AU - Huang, Helen
AU - Greenidge, Gina
AU - Rueda, Oscar M.
AU - Taylor, Adam J.
AU - Karali, Evdoxia
AU - Kazanc, Emine
AU - Spicer, Amy
AU - Dexter, Alex
AU - Lin, Wei
AU - Thompson, Daria
AU - Silva Dos Santos, Mariana
AU - Calvani, Enrica
AU - Legrave, Nathalie
AU - Ellis, James K.
AU - Greenwood, Wendy
AU - Green, Mary
AU - Nye, Emma
AU - Still, Emma
AU - Kreuzaler, Peter
AU - Barry, Simon
AU - Goodwin, Richard J.A.
AU - Bruna, Alejandra
AU - Caldas, Carlos
AU - MacRae, James
AU - de Carvalho, Luiz Pedro Sório
AU - Poulogiannis, George
AU - McMahon, Greg
AU - Takats, Zoltan
AU - Bunch, Josephine
AU - Yuneva, Mariia
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/11
Y1 - 2023/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85176249448&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/37946084
U2 - 10.1038/s42255-023-00915-7
DO - 10.1038/s42255-023-00915-7
M3 - Article
AN - SCOPUS:85176249448
SN - 2522-5812
VL - 5
SP - 1870
EP - 1886
JO - Nature Metabolism
JF - Nature Metabolism
IS - 11
ER -