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Glioblastoma Transcriptomes Point to Mitochondrial Subtype, Potential Treatment Strategies

NEW YORK – An international team led by investigators at Columbia University used a pathway-based analysis of tumor transcriptome data to find four glioblastoma (GBM) subgroups, including a potentially targetable mitochondrial subtype that appears to coincide with better-than-usual outcomes for patients with the aggressive brain tumor.

"The mitochondrial subgroup of GBM exhibits unique sensitivity to inhibitors of mitochondrial metabolism, thus providing insights into the selection of patients with GBM who could benefit from targeted metabolic therapies," co-senior and -corresponding authors Anna Lasorella and Antonio Iavarone of Columbia University and their colleagues wrote in a paper published Monday in Nature Cancer describing the work.

The researchers used single-cell RNA sequences and a new "single-cell biological pathway deconvolution" (scBiPaD) computational pipeline to classify nearly 17,400 individual glioma cells from primary tumors in three-dozen individuals with high-grade glioma. Their analyses highlighted four key subtypes that encompassed more than 90 percent of the GBM cells considered, including neuronal, proliferative/progenitor, mitochondrial, and glycolytic/plurimetabolic subtypes — pathway features that lined up with those found in transcriptome data from hundreds more bulk GBM tumors.

"Two [tumor] classes fall into the functional properties of neuro-development, one recapitulating very immature, progenitor like functions (proliferative-progenitor sub-class) while the other, the neuronal subtype, showing features of more mature cells in the brain, Lasorella, a pediatrics, pathology and cell biology, and cancer genetics researcher at Columbia, explained in an email.

The two developmentally related GBM subtypes tended to turn up in more aggressive tumors, Lasorella said, noting that the team is continuing to investigate that pattern. On the other hand, the remaining two pathway-based subtypes subtypes encompassed tumors with altered metabolic functions, including a group of mitochondrial GBM tumors with recurrent SLC45A1 glucose-proton symporter deletions on chromosome 1.

When investigators brought in available genomic data for another 725 GBM tumors that were wild type for the GBM marker IDH, they uncovered 20 cases involving homozygous SLC45A1 deletions. Along with analyses looking at the alterations that tended to co-occur with those mutations, they showed that the fitness of mitochondrial GBM tumors with SLC45A1 truncations could be blunted by adding the gene back with a lentiviral vector, suggesting the tumors may be vulnerable to enhanced acidity within the cells when the proton pump is active.

And in contrast to tumors from a prognostically poor glycolytic/plurimetabolic subgroup — which includes tumors capable of tapping into a range of energy-producing aerobic glycolysis, amino acid, and lipid metabolism pathways — the researchers saw signs that the mitochondrial tumors are vulnerable to oxidative stress due to their reliance on enhanced mitochondrial activity.

Indeed, the team's subsequent drug sensitivity experiments in dozens of GBM patient-derived cellular models indicated that that the mitochondrial subtype may be sensitive to oxidative phosphorylation (OXPHOS) inhibitors such as metformin, as well as a range of other inhibitors acting on other metabolic stages in the energy-producing organelle.

"[B]eing restricted to mitochondrial activity for energy generation makes the mitochondrial glioblastoma more vulnerable to conditions that impair mitochondrial functions," Lasorella said, adding that "mitochondrial glioblastoma cells were much more sensitive to mitochondrial inhibitors than the other glioblastoma subtypes.

The investigators are continuing to explore such findings in unpublished experiments done in mouse models transplanted with primary mitochondrial GBM subtype tumors, while searching for tumors from still other cancer types that show a similar reliance on mitochondrial metabolic pathways. Still, Lasorella cautioned that promising mitochondrial inhibitor results found so far will ultimately need to be interrogated through clinical studies in GBM.

The team has already come up with a "MTC/GPM activity score" for distinguishing mitochondrial GBM tumors from glycolytic/plurimetabolic with broader metabolic capabilities, which is expected to help find tumors most apt to respond to mitochondrial inhibitors.

"The MTC/GPM activity score may be of general significance in multiple tumor types," the authors concluded, "and will be incorporated in new clinical studies testing the effect of OXPHOS inhibitors in patients with GBM."