Cellular and Molecular Mechanisms of GBM Infiltration

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Summary Glioblastoma (GBM) is the most common and deadly form of primary brain tumor in adults. One feature of GBM that makes it exceedingly difficult to cure is its diffuse infiltration throughout the brain, as treatment, including surgical resection of the primary tumor invariably results in recurrence, often remote from the site of the original tumor. This clinical feature illustrates a key knowledge gap in GBM biology, as the cellular and molecular mechanisms that drive the migration of tumor cells in the brain remain poorly defined. Recent studies have shown that GBM progression is tightly linked to neuronal activity and our preliminary studies show that increased neuronal activity stimulates migration of GBM cells towards hyperactive neurons in the contralateral hemisphere. To decipher the molecular mechanisms driving activity-dependent, GBM infiltration, we performed transcriptomic analysis of these tumors, finding enrichment of axon guidance genes and drastic alterations in immune-related signatures. Functional studies with the axon guidance gene cohort revealed that overexpression of EphA6, EphA7, or Sema4F in mouse GBM promoted infiltration of tumor cells and decreased survival of tumor bearing mice. Similarly, we found decreased CD8-Tcells in response to activity- driven infiltration and preliminary studies suggest that loss of these populations enhances malignant progression. Based on the strength of these preliminary studies we propose three specific aims that seek to uncover the cellular and molecular mechanisms driving GBM infiltration. In aim 1, we will manipulate the activity of subsets of neurons in order to dissect which sub-types of neurons promote GBM infiltration. In aim2, we will determine how EphA6, EphA7, and Sema4F contribute to GBM infiltration and pathophysiology. In aim3, we will determine how neuronal activity influences immune responses, while determining how CD8 T-cells contribute to GBM infiltration. Together, these aims will uncover which neuronal populations promote GBM infiltration, while revealing new roles for axon guidance genes and chemokine receptors in tumor pathophysiology.