Nandhu, Mohan SobhanaKwiatkowska, AnetaBhaskaran, VivekHayes, JosieHu, BinViapiano, Mariano S.2017-12-062017Nandhu, Mohan Sobhana, Aneta Kwiatkowska, Vivek Bhaskaran, Josie Hayes, Bin Hu, and Mariano S. Viapiano. 2017. “Tumor-derived fibulin-3 activates pro-invasive NF-kappa B signaling in glioblastoma cells and their microenvironment.” Oncogene 36 (34): 4875-4886. doi:10.1038/onc.2017.109. http://dx.doi.org/10.1038/onc.2017.109.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492364Molecular 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 NF-κB 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-κB in the tumor and increases NF-κB activation in peritumoral astrocytes. Fibulin-3 expression correlates with a NF-κB-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-κB 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 TNFα by ADAM17, which in turn activates TNF receptors and canonical NF-κB signaling. Taken together, our results underscore fibulin-3 as a novel extracellular signal with strong activating effect on NF-κB in malignant gliomas. Because fibulin-3 is produced de novo in these tumors and is absent from normal brain we propose that targeting the fibulin-3/NF-κB axis may provide a novel avenue to disrupt oncogenic NF-κB signaling in combination therapies for malignant brain tumors.en-UStumor microenvironmentglioma invasionTumor Necrosis Factor alphaExtracellular matrixCYLDTACEADAM17TIMP3Journal Article2017-12-0610.1038/onc.2017.109