A mechanistic model-based analysis of Fn14 - NF-Kappa B dysregulation in glioblastoma multiforme

Fn14 is a transmembrane receptor protein of the tumor necrosis factor receptor (TNFR) superfamily. The protein is found overexpressed in solid tumor cells and its elevated expression is often linked to the progression of glioma patients. The signaling pathway downstream of Fn14 shares many molecular interactions with TNF-α receptor (TNFαR), which is a more well-characterized member of the TNFR family. Nonetheless, reports indicate that these two receptor proteins display considerably distinct response characteristics when stimulated. Crosslinking of Fn14 by its extracellular ligand TWEAK induces prolonged activation of transcription factor NF-κB that sustains for a long period after the ligand exposure. In contrast, TNF-αR engagement of TNFα leads to transient NF-κB activation. This study was directed to understand the molecular mechanisms underlying this distinctive response behavior in Fn14 signaling. A mechanistic model was developed to characterize specific features of the Fn14 pathway that could explain its divergence from TNFαR signaling leading to its elevated expression in glioblastoma. Analysis using the model revealed highly non-linear dynamics in Fn14 signaling, including stable limit cycles and bistable responses depending on the dose and duration of the TWEAK signal. Systematic interrogations using the model identified a positive feedback loop in the Fn14 pathway that may play a crucial role in the prolonged activation of NF-κB and elevated Fn14 expression under specific circumstances. The model-based analyses revealed potential targets for interventions to effectively counteract Fn14 overexpression in tumor progression.