Epigenetically Activated WNT5A Promotes Glioblastoma Progression

Glioblastoma (GBM) stem cells (GSC), which are supported by vascular and hypoxic GSC niches, have been implicated in GBM initiation, progression, and recurrence, and have been shown to transdifferentiate into GSC-derived endothelial cells (GdEC) to promote GBM angiogenesis and growth. To evaluate the role of GdECs in GBM progression, Hu, Wang, Wang, and colleagues generated MYC-immortalized human neural stem cells (MYC-hNSC) expressing dominant-negative TP53 (TP53-DN) and/or constitutively active myristoylated AKT (myr-AKT) to establish a model of de novo GBM. TP53-DN/myr-AKT MYC-hNSCs, but not TP53-DN MYC-hNSCs or myr-AKT MYC-hNSCs, formed classic GBMs in vivo that harbored a self-renewing GSC population that could be differentiated into glial and neuronal lineages and was enriched for endothelial cell (EC) signaling. Further, TP53-DN/myr-AKT MYC-hNSCs, but not TP53-DN MYC-hNSCs, expressed EC markers and gave rise to tubular structures, and transcriptomic analyses revealed that activation of AKT in GSCs increased the fraction of EC marker–positive GSCs and upregulated Wnt family member 5A (WNT5A) and distal-less homeobox 5 (DLX5) to induce the transdifferentiation of GSCs into GdECs. The WNT5A promoter became epigenetically activated during oncogene-induced transformation of immortalized hNSCs, and simultaneous epigenetic silencing of paired box 6 (PAX6), a master regulator of NSC stemness, and epigenetic activation of DLX5 promoted WNT5A activation. Similarly, WNT5A mediated the endothelial differentiation of GSCs to GdECs, which recruited normal ECs to the tumor periphery to establish vascular GSC niches that promote GSC growth and invasion into adjacent normal parenchyma. In patients with GBM, WNT5A expression was correlated with GdEC frequency, and both WNT5A and GdECs were associated with the peritumoral areas of GBM and with GBM recurrence. These findings identify an epigenetic mechanism underlying the endothelial transdifferentiation of GSCs, provide insight into the role of tumor stem cell–derived endothelial cells in GBM pathogenesis, and suggest that WNT5A inhibitors may increase the efficacy of antiangiogenic therapies.

Hu B, Wang Q, Wang YA, Hua S, Sauvé CG, Ong D, et al. Epigenetic activation of WNT5A drives glioblastoma stem cell differentiation and invasive growth. Cell 2016;167:1281–95.