Novel regulation of PDGFRα activation in Glioblastoma

Abstract

Glioblastoma (GBM) is characterized by abnormal activation of receptor tyrosine kinase (RTK) signaling pathways. We demonstrate that the extracellular sulfatase, SULF2, an enzyme that regulates multiple heparan sulfate proteoglycan‐dependent RTK signaling pathways, is a novel regulator of RTK‐signaling in GBM. In primary human GBM SULF2 protein is expressed in 29/57 (50%) tumors and using data from The Cancer Genome Atlas SULF2 transcript is increased in 197/424 (46%) tumors (http://cancergenome.nih.gov). To determine the functional role of SULF2 in GBM we knocked down SULF2 in GBM cell lines and generated murine malignant astrocytomas from Sulf2−/− tumorigenic neurospheres. These data demonstrated a striking SULF2‐dependence in activity of PDGFRα, a major signaling pathway in GBM. Ablation of SULF2 resulted in decreased PDGFRα phosphorylation and decreased downstream MAPK signaling activity. In addition, in vivo tumor growth was decreased. Interestingly, the proneural GBM subtype, characterized by aberrations in PDGFRα, demonstrated the strongest SULF2 expression. SULF2 may help identify a subset of GBMs that may be more dependent on exogenous growth factor‐mediated signaling.This work was supported by funds from the National Institutes of Health (K08 NS063456 to J.J.P.) and the Preuss Foundation.