Investigating Novel Functions for NIK/MAP3K14 in High-Grade Glioma
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PROJECT SUMMARYCancer cells are able to adapt to grow uncontrollably and invasively in environments with limited availabilityof nutrients — most notably, glucose and oxygen. Indeed, the aggressive migration and invasion of high-grade gliomas, including glioblastoma multiforme (GBM), into healthy brain tissue are major factorscontributing to the therapy resistance and poor prognosis of this malignancy. While many cancer cellspreferentially utilize glycolysis to support growth, GBM cells have been shown to rely on both glycolysis andmitochondrial metabolism for glucose energy utilization. Mitochondrial dynamics, or the balance betweenmitochondrial fission and fusion, is a central mechanism for bioenergetic adaptations to cellular stressessuch as nutrient deprvation. Therefore, targeting de-regulated mitochondrial function is a highly attractivetherapeutic strategy for GBM. Recent findings have established key roles for NF-κB-inducing kinase(NIK/MAP3K14) in regulating mitochondrial dynamics and subcellular trafficking to promote theinvasiveness and pathogenesis of GBM cells. Moreover, preliminary data demonstrate that mitochondrialNIK enhances the resistance of GBM cells to nutrient/glucose starvation through regulation of mitochondrialmetabolism. Moreover, the mitochondrial actions of NIK are independent of its regulation of NF-κB activity.However, the molecular mechanisms by which NIK coordinates regulation of mitochondrial function andmetabolic reprogramming in GBM cells are currently not known. This proposal tests the hypothesis that NIKis induced by, and is an important regulator of, mitochondrial dynamics, cancer cell metabolism andinfiltrative growth in response to nutrient deprivation. The goals of the proposal are to functionally defineNIK-dependent regulatory networks and metabolic pathways that regulate cancer cell mitochondrialfunctions and test the whether NIK inhibition will sensitize GBM cells to nutrient starvation and attenuatetumor cell survival and pathogenesis. This proposal is anticipated to have an important positive impactbecause understanding the molecular basis of NIK mitochondrial functions is likely to generate strongjustification for the development of novel, mechanism-based therapies for GBM that target mitochondrialdysfunction, invasion, and de-regulated metabolism through NIK inhibition with the ultimate goal ofimproving patient survival.!