Roles of the NF-kappaB Pathway in Glioblastoma Stem Cells and Chordoma

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Rinkenbaugh, Amanda
- Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine

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The NF-κB pathway consists of a family of five transcription factors: RelA/p65, RelB, c-Rel, p100/p52, and p105/p50. Originally discovered for its involvement in inflammation and immune signaling, aberrant constitutive NF-κB activation is seen in many tumor types. NF-κB-dependent target gene regulation mediates several hallmarks of cancer, including survival, suppression of apoptosis, and invasion. This work examines NF-κB signaling in both glioblastoma and chordoma samples. In the first project, NF-κB is found to mediate cancer stem cell maintenance in glioblastoma explants. Both genetic and pharmacological NF-κB inhibition impair neurosphere formation at limiting dilutions. Use of an ex vivo brain slice co-culture model confirmed the in vitro findings, providing a novel platform for drug testing in glioblastoma studies that bridges the gap between cell culture and intracranial animal models. In the second project, NF-κB regulates proliferation and invasion of chordoma cell lines. Due to the rarity of chordomas, these tumors have not been well- characterized at a molecular level. These results provide some of the early evidence for NF- κB activation, potentially through regulation of IL-6, IL-8, and MMP9. Both of these studies suggest that IKK/NF-κB inhibition could provide therapeutic benefit in glioblastoma and chordoma, affecting multiple phenotypes that drive the poor prognosis of these tumors.

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