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Genes Dev. 2017 Sep 1;31(17):1738-1753. doi: 10.1101/gad.302349.117. Epub 2017 Sep 26.

TAp73 is a marker of glutamine addiction in medulloblastoma.

Author information

1
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom.
2
Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry, Uppsala University, 751 23 Uppsala, Sweden.
3
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany.
4
Department of Neuropathology, Medical Faculty, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany.
5
Department of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
6
Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom.
7
University College London, Institute of Child Health, London WC1N 1EH, United Kingdom.
8
Medical Product Agency, SE-751 03 Uppsala, Sweden.
9
Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, United Kingdom.

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 xenograft 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.

KEYWORDS:

glutamine; medulloblastoma; metabolomics; p73

PMID:
28971956
PMCID:
PMC5666673
DOI:
10.1101/gad.302349.117
[Indexed for MEDLINE]
Free PMC Article

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