(520e) Direct Contact with Astrocytes Drives Metabolic Reprogramming in Glioblastoma Multiforme Cells

Glioblastoma Multiforme (GBM) is the most common and aggressive malignant brain tumor in the United States with an extremely poor clinical prognosis. GBM has an age-adjusted incidence rate of 3.2 cases per 100,000 population and more than 13,000 cases projected in 2021. Among older adults, the incidence rate is higher, with 15.28 cases per 100,000 population of 75–84 year-olds. The median survival time after a GBM diagnosis is less than 18 months and fewer than 7% of patients survive more than 5 years. Developments in surgical resection and chemotherapy have improved survival time by 150% from less than 10 months in the 1970s to approximately 15 months in the early 2000s, but median survival has remained statistically unchanged since. Therefore, it remains that a more thorough understanding of GBM-centric biology is crucial in the improving clinical outcomes for GBM patients.

GBM tumors often arise from astrocytes or other glial cells and are characterized by their invasion into surrounding tissues and recruitment of healthy tissues into tumor tissue. Astrocytes, the most abundant glial cell in the brain, primarily function to maintain ion homeostasis and modulate energy production through both direct and indirect communication. Modulation of GBM cell metabolism is associated with the aggressiveness, and thereby mortality, associated with the tumor, however the underlying mechanisms that attribute to distinct aspects of GBM metabolism remain unknown. We postulate that physical contact with astrocytes is altering GBM metabolism and, in order to investigate this hypothesis, engineer a novel, protein-free, patterned co-culture system for astrocytes and glioma cells.

Here, we demonstrate that the physical contact of GBM cells with astrocytes is a potential modulator of metabolic reprogramming in glioma cells. Using layer-by-layer assembly and microcapillary-force driven in vitro patterning, we find that physical contact with astrocytes results in significant upregulation in energy utilization of glioblastoma cells when grown in co-culture with astrocytes compared to both transwell co-culture and glioma cells grown in monoculture.

Beyond this, we also show a significant change in metabolism related and signaling-related proteins and a significant upregulation of the transcription of genes involved in energy metabolism. Taken together, these results indicate a more aggressive glioma phenotype when cells are in physical contact with astrocytes thereby suggesting that astrocytes are potent mediators of metabolic reprogramming in glioma cells and could reveal targets to treat GBM patients.