Duran, Camille L (2017-05). Noncanonical NF-KB Signaling Drives Glioma Invasion by Promoting MT1-MMP Activation, Pseudopodia Formation, and ITGA11 Expression. Doctoral Dissertation. Thesis uri icon

abstract

  • A hallmark of high grade glioma is highly aggressive, diffuse invasion into normal brain tissue, contributing to a 100% recurrence rate and resistance to current therapies. Recent efforts to determine molecular differences in high grade glioma and define tumor subtypes have revealed that the noncanonical NF-KB transcription factor RelB is upregulated in the highly aggressive mesenchymal subtype, as well as in recurrent tumors. The studies presented here seek to better understand how noncanonical NF-KB signaling drives glioma cell invasion in a three-dimensional (3D) environment. Stabilization of NF- KB-inducing kinase (NIK), a critical driver of noncanonical NF-KB signaling, promoted glioma cell adhesion, spreading, and pseudopodia formation on collagen, which is expressed at low levels in normal brain tissue but highly upregulated within the stroma and surrounding tissue of glioma. As NIK expression appeared to regulate glioma cell behavior on collagen, we investigated whether NIK controls the expression of integrins known to bind collagen. We found NIK expression upregulated the integrin alpha 11 subunit (ITGA11), while it did not significantly affect the expression of ITGA1, ITGA2, or ITGA10. Analysis of human tumor samples revealed that ITGA11 expression was increased in glioma tissue compared to normal brain tissue. Furthermore, when testing multiple glioma lines, ITGA11 expression positively correlated with invasiveness into 3D collagen matrices. Investigation of a key transmembrane metalloproteinase revealed that NIK expression enhanced the localization of active, phosphorylated membrane-type 1 matrix metalloproteinase (MT1-MMP) to pseudopodial structures. In a heterologous system, ITGA11 and MT1-MMP formed a complex, suggesting these transmembrane proteins could interact in glioma cells to facilitate coordinated recognition and degradation of collagen during invasion. Finally, silencing of ITGA11 in an invasive glioma line attenuated invasion into 3D collagen matrices. Collectively, these data reveal an ability of NIK to promote directed glioma cell invasion, pseudopodia formation, ITGA11 expression, and activated MT1-MMP localization to pseudopodia. These data suggest ITGA11 could serve as a novel marker for more invasive glioma and a potential therapeutic target in glioma.

publication date

  • May 2017