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.
Highlights
Medulloblastoma is the most common solid primary brain tumor in children
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
TAp73 is overexpressed in MB and controls proliferation in MB cell lines and patient-derived primary cells p73 was reported to be overexpressed in MB (Zitterbart et al 2007), it was unclear which p73 isoforms were expressed
Summary
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. 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. Glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. Current treatment strategies include a combination of surgery, radiotherapy, and chemotherapy, which have achieved 70%–80% 5-yr survival rates; recurrence is common and often proves fatal (Hill et al 2015). Both the brain exposure to ionizing radiation and the systemic exposure to chemotherapy agents can induce severe side effects, leading to mental and physical disability of the affected children. The p53 family comprises three members (p53, p63, and p73) (Boominathan 2010), and its role in promoting cell
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