Glioblastoma tumor microtubes and brain fatty acid-binding protein: Path to directional infiltration

Abstract

Background. Glioblastoma (GBM) is a deadly brain cancer with a dismal prognosis. There is evidence that infiltration and therapy resistance in GBM are driven by tumor microtubes (TMs), ultra-long membrane-enclosed protrusions that serve as intercellular communication channels. The aims of this study were to investigate the role of TMs and identify the molecular drivers involved in TM formation. Methods. We used patient-derived GBM neurosphere cultures that produce TMs to investigate TM dynamics, the proteins and pathways involved in TM formation, and the effect of targeting brain fatty acid-binding protein (FABP7) on mouse survival using an orthotopic model of GBM. Results. The radial glial cell marker, FABP7, is highly expressed in TMs. Like GAP43, FABP7 is critically important for the formation of TMs in GBM neurosphere cultures. We show that GBM cells use TMs as a fiber network for rapid and directional migration. Our results indicate that GAP43 phosphorylation is required for TM formation, with GAP43 phosphorylation facilitated by FABP7 expression. We also show that depletion or inhibition of protein kinase C (PKC), the kinase responsible for GAP43 phosphorylation, decreases TM formation. Targeting FABP7 in an orthotopic mouse model of TM-forming GBM cells increases survival but does not sensitize tumors to radiation. Conclusions. We found that the FABP7-PKC-pGAP43 axis is key to GBM TM formation, with TMs serving as networks for efficient long-distance cell migration. Our results indicate that TM formation can be mitigated by FABP7 inhibition with the potential of improving clinical outcomes in GBM patients.