75 Fatty Acid Binding Protein 7 Modulates PKC-dependent Tumour Microtube Formation in Glioblastoma

Abstract Introduction Glioblastoma is the most common primary malignant brain tumour, accounting for ∼60% of central nervous system malignancies. In spite of treatment with surgery, radiation, and temozolomide (TMZ), prognosis remains poor with a five-year survival rate below 5%. Recurrence and treatment resistance are thought to be driven by glioblastoma stem-like cells (GSCs), which form tumour microtubes (TMs): ultralong protrusions that facilitate migration and confer treatment resistance. TMs are enriched for Growth Associated Protein-43 (GAP-43), and phosphorylation of GAP-43 at a PKC-specific phosphosite has been implicated in TM formation. It has been shown that TMZ induces TM formation in resistant GSCs; however, upstream regulators remain unclear. GSCs highly express Fatty Acid Binding Protein 7 (FABP7), a lipid chaperone that binds arachidonic acid, a known activator of PKC. We hypothesize that TMZ promotes TM formation through FABP7-dependent modulation of PKC-regulated GAP-43 phosphorylation. Method Three patient-derived GSC neurosphere lines were treated with TMZ combined with a PKC inhibitor or an FABP7 inhibitor. TM formation was assessed by light microscopy, while GAP-43 phosphorylation and PKC expression were evaluated by Western blot and immunofluorescence. Results TMZ increased TM formation across all lines, accompanied by elevated GAP-43 phosphorylation. Pharmacologic inhibition of PKC or FABP7 significantly attenuated TMZ-induced TM formation and reduced GAP-43 phosphorylation. Conclusions Together, these findings support a model in which TMZ-associated TM formation is regulated through a putative FABP7–PKC–GAP-43 signaling axis. This pathway provides mechanistic insight into glioblastoma therapeutic resistance. These results identify FABP7 as a druggable target warranting further validation in organoid and orthotopic systems. Targeting FABP7 may represent a strategy to limit TM-mediated therapeutic resistance, reduce invasive capacity, and improve treatment responsiveness in glioblastoma in future translational and clinical studies.