| First Author | Nandhu MS | Year | 2017 |
| Journal | Oncogene | Volume | 36 |
| Issue | 34 | Pages | 4875-4886 |
| PubMed ID | 28414309 | Mgi Jnum | J:248155 |
| Mgi Id | MGI:5925622 | Doi | 10.1038/onc.2017.109 |
| Citation | Nandhu MS, et al. (2017) Tumor-derived fibulin-3 activates pro-invasive NF-kappaB signaling in glioblastoma cells and their microenvironment. Oncogene 36(34):4875-4886 |
| abstractText | Molecular profiling of glioblastomas has revealed the presence of key signaling hubs that contribute to tumor progression and acquisition of resistance. One of these main signaling mechanisms is the nuclear factor-kappa B (NF-kappaB) pathway, which integrates multiple extracellular signals into transcriptional programs for tumor growth, invasion and maintenance of the tumor-initiating population. We show here that an extracellular protein released by glioblastoma cells, fibulin-3, drives oncogenic NF-kappaB in the tumor and increases NF-kappaB activation in peritumoral astrocytes. Fibulin-3 expression correlates with a NF-kappaB-regulated 'invasive signature' linked to poorer survival, being a possible tissue marker for regions of active tumor progression. Accordingly, fibulin-3 promotes glioblastoma invasion in a manner that requires NF-kappaB activation both in the tumor cells and their microenvironment. Mechanistically, we found that fibulin-3 activates the metalloprotease ADAM17 by competing with its endogenous inhibitor, TIMP3. This results in sustained release of soluble tumor necrosis factor alpha (TNFalpha) by ADAM17, which in turn activates TNF receptors and canonical NF-kappaB signaling. Taken together, our results underscore fibulin-3 as a novel extracellular signal with strong activating effect on NF-kappaB in malignant gliomas. Because fibulin-3 is produced de novo in these tumors and is absent from the normal brain, we propose that targeting the fibulin-3/NF-kappaB axis may provide a novel avenue to disrupt oncogenic NF-kappaB signaling in combination therapies for malignant brain tumors. |
