TY - JOUR
T1 - Metabolic rewiring in MYC-driven medulloblastoma by BET-bromodomain inhibition
AU - Graziani, Vittoria
AU - Rodriguez Garcia, Aida
AU - Sainero Alcolado , Lourdes
AU - Le Guennec, Adrien
AU - Arsenian Henriksson, Marie
AU - Conte, Maria R
N1 - Funding Information:
We are grateful to Associate Professor JI Johnsen, Karolinska Institutet, for generously sharing the MB cell lines. This research was supported by the Swedish Research Council, the Swedish Cancer Society, the Swedish Childhood Cancer Fund, Radiumhemmet Research Funds, and Karolinska Institutet to MAH. NMR experiments and analysis were performed in the Centre for Biomolecular Spectroscopy, King’s College London, which was established with funds to MRC from Wellcome and British Heart Foundation, ref. 202767/Z/16/Z and BHF-IG/16/2/32273. VG was supported by a scholarship from Radiumhemmet, Stockholm and ARG by a postdoctoral position from the Swedish Cancer Society.
Funding Information:
We are grateful to Associate Professor JI Johnsen, Karolinska Institutet, for generously sharing the MB cell lines. This research was supported by the Swedish Research Council, the Swedish Cancer Society, the Swedish Childhood Cancer Fund, Radiumhemmet Research Funds, and Karolinska Institutet to MAH. NMR experiments and analysis were performed in the Centre for Biomolecular Spectroscopy, King’s College London, which was established with funds to MRC from Wellcome and British Heart Foundation, ref. 202767/Z/16/Z and BHF-IG/16/2/32273. VG was supported by a scholarship from Radiumhemmet, Stockholm and ARG by a postdoctoral position from the Swedish Cancer Society.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Medulloblastoma (MB) is the most common malignant brain tumour in children. High-risk MB patients harbouring MYC amplification or overexpression exhibit a very poor prognosis. Aberrant activation of MYC markedly reprograms cell metabolism to sustain tumorigenesis, yet how metabolism is dysregulated in MYC-driven MB is not well understood. Growing evidence unveiled the potential of BET-bromodomain inhibitors (BETis) as next generation agents for treating MYC-driven MB, but whether and how BETis may affect tumour cell metabolism to exert their anticancer activities remains unknown. In this study, we explore the metabolic features characterising MYC-driven MB and examine how these are altered by BET-bromodomain inhibition. To this end, we employed an NMR-based metabolomics approach applied to the MYC-driven MB D283 and D458 cell lines before and after the treatment with the BETi OTX-015. We found that OTX-015 triggers a metabolic shift in both cell lines resulting in increased levels of myo-inositol, glycerophosphocholine, UDP-N-acetylglucosamine, glycine, serine, pantothenate and phosphocholine. Moreover, we show that OTX-015 alters ascorbate and aldarate metabolism, inositol phosphate metabolism, phosphatidylinositol signalling system, glycerophospholipid metabolism, ether lipid metabolism, aminoacyl-tRNA biosynthesis, and glycine, serine and threonine metabolism pathways in both cell lines. These insights provide a metabolic characterisation of MYC-driven childhood MB cell lines, which could pave the way for the discovery of novel druggable pathways. Importantly, these findings will also contribute to understand the downstream effects of BETis on MYC-driven MB, potentially aiding the development of new therapeutic strategies to combat medulloblastoma.
AB - Medulloblastoma (MB) is the most common malignant brain tumour in children. High-risk MB patients harbouring MYC amplification or overexpression exhibit a very poor prognosis. Aberrant activation of MYC markedly reprograms cell metabolism to sustain tumorigenesis, yet how metabolism is dysregulated in MYC-driven MB is not well understood. Growing evidence unveiled the potential of BET-bromodomain inhibitors (BETis) as next generation agents for treating MYC-driven MB, but whether and how BETis may affect tumour cell metabolism to exert their anticancer activities remains unknown. In this study, we explore the metabolic features characterising MYC-driven MB and examine how these are altered by BET-bromodomain inhibition. To this end, we employed an NMR-based metabolomics approach applied to the MYC-driven MB D283 and D458 cell lines before and after the treatment with the BETi OTX-015. We found that OTX-015 triggers a metabolic shift in both cell lines resulting in increased levels of myo-inositol, glycerophosphocholine, UDP-N-acetylglucosamine, glycine, serine, pantothenate and phosphocholine. Moreover, we show that OTX-015 alters ascorbate and aldarate metabolism, inositol phosphate metabolism, phosphatidylinositol signalling system, glycerophospholipid metabolism, ether lipid metabolism, aminoacyl-tRNA biosynthesis, and glycine, serine and threonine metabolism pathways in both cell lines. These insights provide a metabolic characterisation of MYC-driven childhood MB cell lines, which could pave the way for the discovery of novel druggable pathways. Importantly, these findings will also contribute to understand the downstream effects of BETis on MYC-driven MB, potentially aiding the development of new therapeutic strategies to combat medulloblastoma.
UR - http://www.scopus.com/inward/record.url?scp=85146793197&partnerID=8YFLogxK
U2 - 10.1038/s41598-023-27375-z
DO - 10.1038/s41598-023-27375-z
M3 - Article
SN - 2045-2322
VL - 13
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 1273
ER -
