Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo.
Dysregulated metabolism is a hallmark of cancer cell lines, but little is known about the fate of glucose and other nutrients in tumors growing in their native microenvironment. To study tumor metabolism in vivo, we used an orthotopic mouse model of primary human glioblastoma (GBM). We infused (13)C-labeled nutrients into mice bearing three independent GBM lines, each with a distinct set of mutations. All three lines displayed glycolysis, as expected for aggressive tumors. They also displayed unexpected metabolic complexity, oxidizing glucose via pyruvate dehydrogenase and the citric acid cycle, and using glucose to supply anaplerosis and other biosynthetic activities. Comparing the tumors to surrounding brain revealed obvious metabolic differences, notably the accumulation of a large glutamine pool within the tumors. Many of these same activities were conserved in cells cultured ex vivo from the tumors. Thus GBM cells utilize mitochondrial glucose oxidation during aggressive tumor growth in vivo.
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Isaac
I
Marin-Valencia
Chendong
C
Yang
Tomoyuki
T
Mashimo
Steve
S
Cho
Hyeonman
H
Baek
Xiao-Li
XL
Yang
Kartik N
KN
Rajagopalan
Melissa
M
Maddie
Vamsidhara
V
Vemireddy
Zhenze
Z
Zhao
Ling
L
Cai
Levi
L
Good
Benjamin P
BP
Tu
Kimmo J
KJ
Hatanpaa
Bruce E
BE
Mickey
José M
JM
Matés
Juan M
JM
Pascual
Elizabeth A
EA
Maher
Craig R
CR
Malloy
Ralph J
RJ
Deberardinis
Robert M
RM
Bachoo
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism*; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D005972:Glutaminase / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism*; D009368:Neoplasm Transplantation; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D010641:Phenotype; D011766:Pyruvate Carboxylase / Q000378:metabolism; D018709:Statistics, Nonparametric; D014407:Tumor Cells, Cultured
D005973:Glutamine; D018698:Glutamic Acid; D005972:Glutaminase; D005974:Glutamate-Ammonia Ligase; D011766:Pyruvate Carboxylase; D005947:Glucose