TMOD-48. SNAIL1 REGULATES GLIOMAGENESIS INDEPENDENT OF ITS MESENCHYMAL TRANSFORM FUNCTION

Abstract

BACKGROUND

Master mesenchymal factors such as Snail1 have long been implicated in local invasion and metastasis of various cancers including malignant brain tumors such as glioblastoma (GBM). However, mesenchymal factors are expressed early in tumorigenesis, well before first evidence of metastatic cells, suggesting that these factors have other critical functions independent of their mesenchymal regulation.

METHODS

We used a highly penetrant, retrovirally-delivered, PDGFB-induced mouse model of gliomagenesis in a conditional PTEN and/or P53 knockout background to produce GBM tumors of the proneural subtype, in which Snail1 expression is much lower compared to the mesenchymal subtype. We then examined the effect of conditional KO of Snail1 in glial cells when PDGFB overexpression occurred, using in vitro and in vivo loss-of-function experiments augmented by RNAseq expression profiling and computational network analysis.

RESULTS

Snail1 expression peaked early in gliomagenesis although its expression is downregulated once PDGFB-induced proneural tumors are formed. In an immune intact background, Snail1-null GBM developed at a much slower pace. Snail1 cooperated with oncogene activity to promote higher transformative capacity and to influence the cancer stem cell compartment.

CONCLUSION

Our data confirms a dual role for Snail1 in GBM progression, in which it cooperates with oncogenes to promote early transformation while independently also regulating mesenchymal changes at later stages of tumor development. Our platform combining RNAseq expression profiling and computational network analysis with biological validation provides a potentially powerful tool to study mechanistic events as gliomagenesis and proneural subtype GBM transformed into mesenchymal subtype GBM.