Metabolic mechanisms of glioma progression

PROJECT SUMMARY Gliomas represent 80% of the 26,000 newly diagnosed cases of malignant brain and central nervous system tumors in the United States each year and are among the most lethal and treatment-resistant human cancers. There are no curative treatments for glioma, and high-grade gliomas carry a particularly dismal prognosis, with a median overall survival of just 16 months. Therefore, there is a dire need to generate new insights into the pathological mechanisms driving glioma formation and progression and translate this information into new treatment strategies. Despite advances in our understanding of the transcriptional and genomic aberrations associated with this disease, our knowledge of the metabolic alterations that define distinct subsets of glioma is relatively limited. To address this issue, we performed mass spectrometry-based quantification of 564 unique metabolites in a collection of 91 adult surgical brain tissue specimens, representing high-grade gliomas, lower- grade gliomas, brain metastases, and non-malignant brain tissue. We found evidence of widespread reprogramming of an anabolic metabolism pathway in high-grade gliomas relative to lower-grade gliomas and non-malignant brain specimens. Intriguingly, metabolic reprogramming in high-grade gliomas displayed clear parallels with a well characterized inborn error of metabolism. In patients with congenital mutations affecting this pathway, aberrant metabolite secretion from neural cells causes neuronal hyperexcitability and leads to seizures that characterize this disease. Local neuronal hyperexcitability and seizures are also features of high- grade gliomas. In these tumors, neurons communicate with tumor cells through paracrine signaling and electrochemical stimulation mechanisms that promote glioma growth. In turn, glioma cells signal to neurons to foster their excitability, albeit through mechanisms that are not fully understood. Based on these findings, we hypothesize that aberrant metabolite secretion represents a key mechanism underlying glioma-neuron crosstalk in high-grade gliomas and that this phenotype is crucial for brain tumor progression. We will test this hypothesis through three specific aims. First, we will dissect the molecular basis for metabolic reprogramming and aberrant metabolite secretion in high-grade gliomas, testing the idea that imbalanced enzyme expression is necessary and sufficient to trigger these events. Second, we will determine the impact of aberrant metabolite secretion by glioma cells on excitability of the tumor microenvironment by measuring neuronal activity and glioma cell depolarization. Third, we will define the role of metabolic reprogramming and aberrant metabolite secretion in glioma pathogenesis by deactivating these mechanisms and evaluating the effect on intracranial glioma xenograft growth. Together, these studies may reveal a new intercellular communication pathway linking glioma cells and neurons, representing a vulnerability that could be exploited for brain tumor therapy.