Reprograming of cellular metabolism is a hallmark of
cancer. Altering metabolism allows
cancer cells to overcome unfavorable microenvironment conditions and to proliferate and invade.
Medulloblastoma is the most common malignant
brain tumor of children. Genomic amplification of MYC defines a subset of poor-prognosis
medulloblastoma. We performed comprehensive metabolic studies of human MYC-amplified
medulloblastoma by comparing the metabolic profiles of
tumor cells in three different conditions-in vitro, in flank xenografts and in orthotopic xenografts in the cerebellum. Principal component analysis showed that the metabolic profiles of brain and flank high-MYC
medulloblastoma tumors clustered closely together and separated away from normal brain and in vitro MYC-amplified cells. Compared to normal brain, MYC-amplified
medulloblastoma orthotopic xenograft
tumors showed upregulation of the TCA cycle as well as the synthesis of
nucleotides,
hexosamines,
amino acids and
glutathione. There was significantly higher
glucose uptake and usage in orthotopic xenograft
tumors compared to flank xenograft
tumors and cells in culture. In orthotopic
tumors,
glucose was the main
carbon source for the de novo synthesis of
glutamate,
glutamine and
glutathione through the TCA cycle. In vivo, the
glutaminase II pathway was the main pathway utilizing
glutamine.
Glutathione was the most abundant upregulated metabolite in orthotopic
tumors compared to normal brain.
Glutamine-derived
glutathione was synthesized through the
glutamine transaminase K (GTK)
enzyme in vivo. In conclusion, high MYC
medulloblastoma cells have different metabolic profiles in vitro compared to in vivo, and key vulnerabilities may be missed by not performing in vivo metabolic analyses.