TMOD-14CHARACTERIZING SIGNALING PATHWAYS IN A MOUSE MODEL OF GLIOBLASTOMA

INTRODUCTION: Glioblastoma (GBM) is a fatal brain cancer, characteristically ‘driven’ by mutations in multiple tyrosine kinase and tumour suppressor pathways. We have developed a new murine model of GBM in which the sequence of molecular events and signaling pathways that underlie human GBM can be explored. In our model, cells from the subventricular zone (SVZ) of p53-/- mice become growth factor independent when cultured in serum-free media supplemented with platelet-derived growth factor-AA (PDGF-AA). When these cells are implanted into the brains of immune-competent p53 wild-type mice they form tumours that closely resemble human GBM. Here, we explored the mechanism of sustained cell proliferation in the transformed state. METHODS: Phospho-receptor tyrosine kinase (RTK) arrays were used to evaluate RTK phosphorylation, non-RTK arrays to examine pathway activation, and PDGFR-α inhibitors to assess the role of PDGFR-α in sustaining cell viability in pre-transformed and transformed cells. RESULTS: PDGFR-α was phosphorylated in pre-transformed SVZ cells and remained phosphorylated in transformed cells proliferating in the absence of exogenous PDGF-AA. An inhibitor of PDGFR-α that blocked PDGF-AA binding decreased the viability of pre-transformed SVZ cells but had no effect on transformed cells. In contrast, Imatinib, an inhibitor of PDGFR-α phosphorylation, blocked the proliferation of both. Downstream proteins, ERK1/2 and WNK1, and the transcription factor, CREB, were activated in transformed cells. CONCLUSION: In a PDGF-AA initiated mouse model of GBM, exogenous growth factor independent proliferation of p53-null SVZ cells and tumorigenicity are associated with persistent phosphorylation (i.e., activation) of PDGFR-α. The finding that transformed cells are insensitive to inhibition by a PDGFR-α blocking antibody, but respond to Imatinib, is consistent with receptor autophosphorylation. These observations may be applicable to human GBM where over-expression of PDGF-AA appears to be an early event in the pathogenesis of proneural and other subtypes of GBM.

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