NIK Promotes a Leader Cell Phenotype in Glioma
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PROJECT SUMMARY:No cure currently exists for high grade gliomas, which have a mean survival time ofapproximately 1 year from diagnosis. These tumors are highly aggressive and invasive,despite current treatment protocols. Noncanonical NF-ÎºB signaling has been linked toglioma progression, but the downstream consequences of activation of this pathwayhave not been completely defined. Thus, a better understanding of the key molecularsignals that regulate the invasive nature of glioma could aid in intervening in theseclinical situations. This proposal will examine whether the NF-ÎºB-inducing kinase (NIK)enhances the leader cell phenotype in glioma to increase collective cell migration, whichfacilitates tumor invasion of surrounding normal tissue. Based on previous andpreliminary findings, we hypothesize that NIK and noncanonical NF-ÎºB signalingpromotes the acquisition of invasive potential in leader cells responsible for tumordissemination through upregulation of the Î±11 integrin subunit (ITGA11) and MT1-MMPactivity. The enclosed aims will test whether noncanonical NF-ÎºB signaling enhancesITGA11 expression and pseudopodial localization, and also determine the functionalsignificance of noncanonical NF-ÎºB controlled ITGA11 expression on glioma cellinvasion. We will use complementary approaches that involve the use of primary humanbrain tumor lines in vitro and in vivo. These studies are expected to show that NIK andnoncanonical NF-ÎºB signaling simultaneously enhances ECM recognition anddegradation via ITGA11/MT1-MMP complexes in the mesenchymal subtype of glioma tofacilitate tumor dissemination. These studies will contribute to our long-term goal of animproved understanding of the molecular signals that initiate cell migration in three-dimensions and glioma progression.