Abstract
Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xeno-graft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma.
| Original language | English |
|---|---|
| Pages (from-to) | 1738-1753 |
| Number of pages | 16 |
| Journal | Genes and Development |
| Volume | 31 |
| Issue number | 17 |
| DOIs | |
| Publication status | Published - 1 Sept 2017 |
Funding
1Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom; 2Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry, Uppsala University, 751 23 Uppsala, Sweden; 3Department of Pediatric Oncology, Hematology, and Clinical Immunology, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; 4Department of Neuropathology, Medical Faculty, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; 5Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; 6Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom; 7University College London, Institute of Child Health, London WC1N 1EH, United Kingdom; 8Medical Product Agency, SE-751 03 Uppsala, Sweden; 9Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, United Kingdom We are grateful to Patrick Pallier, Xinyu Zhang, Thomas Millner, Ashirwad Merve, Anthony Price, and Samuel Carney for their helpful advice, and Peter Dirks and Xiao-Nan Li for the gift of patient-derived low-passage MB cells. This work was funded by a Children with Cancer UK fellowship (reference no. 2014/178) awarded to M.V.N.-C., a Medical Research Council UK project grant (MR/N000528/1) to S.M., and a Medical Research Council UK Programme grant to G.M. M.V.N.-C., P.H.R.M., and M.H. conducted the experiments. M.V.N.-C., D.M., G.M., and S.M. designed the experiments and wrote the paper. D.P. and M.R. performed the RNA-seq analysis. M.S., D.W., and S.C.C. performed the analysis of p73 levels in the human MB data set. I.E., M.E., J.H., T.A., and C.P. performed the metabolomics analysis.
Keywords
- Glutamine
- Medulloblastoma
- Metabolomics
- P73
ASJC Scopus subject areas
- Genetics
- Developmental Biology