Nuclear translocation matters: Role of FABP7 in driving glioblastoma stemness and invasion: Reply to Mu et al.

We thank Mu et al. for their interest in our recent publication on the role of a FABP7-RXRα neurogenic pathway in driving migratory and infiltrative glioblastoma stem cells. Mu et al. indicate that data mining of the Ivy-GAP glioblastoma database1 and a single-cell RNA-seq dataset2 failed to reveal increased expression of FABP7 in the infiltrating areas of the tumors compared to the tumor center. With regards to the Ivy-GAP dataset, one must take into consideration the stated ratio of tumor to nontumor cells in infiltrating areas compared to the cellular tumor. According to the Ivy-GAP database, ~10%–20% of cells in the infiltrating areas are tumor cells. In contrast, the cellular core consists primarily of tumor cells. It may, therefore, not be surprising that FABP7 expression is not increased in the infiltrative areas of the tumor as few adult brain cells express FABP7. While the single-cell RNA-seq data showed no increase in FABP7 RNA levels in the infiltrating regions of the tumor, FABP7 protein levels and subcellular distribution need to be taken into consideration. As also reported by others, our glioblastoma tissue microarray analysis indicates that nuclear rather than cytoplasmic FABP7 protein levels correlate with a worse patient outcome.3 We show that FABP7 facilitates activation of the nuclear receptor retinoid-X-receptor alpha (RXRα), which in turn mediates the action of FABP7 in migratory glioblastoma stem cells, providing insight into the role of nuclear FABP7 in glioblastoma aggressiveness. In general, in agreement with the increased cell migration observed with the scratch assay, our in vivo models reveal an association between FABP7-expressing cells, tumor expansion, and tumor infiltration.3 Intraperitoneal injection of the FABP7 inhibitor, SBFI-26, reduces tumor cell infiltration in mice intracranially implanted with glioblastoma stem cells,3,4 suggesting that SBFI-26 does cross the blood–brain barrier. Our study further demonstrates that SBFI-26 inhibits FABP7-induced phenotypes in glioblastoma stem cells in vitro (self-renewal capacity and SOX2 induction).3 We are aware that SBFI-26 also targets FABP5, as does MF6, the novel FABP7 inhibitor mentioned by Mu et al. We agree that new specific inhibitors of FABP7 that cross the blood–brain barrier will need to be developed for therapeutic use. Omega-3 docosahexaenoic acid (DHA) and omega-6 arachidonic acid (AA) are preferred ligands of FABP7. Considering the different effects of DHA and AA on the cell membrane5 and growth properties of FABP7-expressing glioblastoma cells,6 as well as the contrasting prognostic significance of cytoplasmic versus nuclear levels of FABP7 in glioblastoma, FABP7 likely plays different roles depending on its subcellular localization. In consideration of the reduced DHA:AA ratio in the glioblastoma tumor microenvironment, we are currently investigating how DHA supplementation might be used to mitigate the aggressive properties of FABP7 glioblastoma stem cells. As indicated by Mu et al., the well-established FABP7-negative U87 malignant glioma cell line, likely derived from a patient with glioblastoma, does not show the typical infiltrative behavior associated with patient-derived glioblastoma cells cultured under neurosphere conditions. As all glioblastoma neurosphere cultures that we have tested to date express FABP7, we used the U87 cell line to examine the effect of ectopic expression of FABP7 on glioma growth properties. As shown in our paper,3 FABP7 expression in U87 significantly increased cell migration in vitro and invasive properties in vivo. In recognition of the limitation of the U87 malignant glioma cell line, we also used 2 patient-derived glioblastoma stem cell cultures (A4-004, A4-007) as well as a tissue microarray from glioblastoma patients for our studies. Our paper highlights the importance of an FABP7-mediated neurogenic program in migrating glioblastoma stem cells. Further characterization of FABP7 and the interplay with its ligands may open new avenues for targeting FABP7-mediated glioblastoma infiltration. Canadian Institutes of Health Research (#190313). Conflict of interest statement None declared.

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