AI-06 * NON-CANONICAL NF-kB SIGNALING DRIVES THE AGGRESSIVE INVASIVENESS OF GLIOBLASTOMA

Abstract

The aggressive migration and invasion of glioblastoma multiforme (GBM) cells into healthy brain tissue are major factors contributing to the therapy resistance and poor prognosis of this malignancy. Aberrant activation of NF-kB has been shown to play key roles in the invasiveness and pathogenesis of many cancers, including GBM. Most of these studies have focused on canonical NF-kB signaling, which is mediated by RelA and p50. Activation of the canonical NF-kB pathway is induced by IkB kinase-b (IKKb), whose inhibition has been pursued as a therapeutic approach to attenuate NF-kB activation in cancer with limited success to-date. We have recently shown that the alternative, or non-canonical, NF-kB signaling pathway mediated by RelB, predominates in a very aggressive GBM subtype. Here, we investigate this previously unrecognized role for non-canonical NF-kB signaling in CNS tumor initiation and progression. Using both established and primary GBM tumor lines, we show that in high RelB-expressing GBM cells, loss of RelB inhibits invasion to a greater extent than loss of RelA. Furthermore, RelB expression is sufficient to promote invasion in RelA-deficient GBM cells. Stimulation with Tumor Nectosis Factor Weak Inducer of Apoptosis (TWEAK) preferentially activates non-canonical NF-kB signaling and regulation of Matrix Metalloproteinase 9 (MMP9) expression, resulting in strongly increased invasion. Finally, we show that a key upstream regulator of RelB, NF-kB-inducing kinase (NIK), induces dramatic cell shape changes, increases tumor cell invasion and promotes aggressive orthotopic tumor growth in mouse xenografts. These results not only expand on previously described roles for TWEAK in promoting tumor cell survival, but also demonstrate a potent pro-invasion function for NIK in aggressive GBM and, potentially, other RelB-driven tumors. Notably, oncogenic functions of the non-canonical NF-kB pathway remain poorly elucidated in the CNS. Our data highlight the therapeutic potential of targeting NIK in GBM.