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Role of FOXP1 in glioblastoma multiforme

Amy Haseley Thorne

Appointment Period: 2015-2017, Grant Years: [29, 30]

Amy Haseley Thorne

Glioblastoma multiforme is one of the most devastating primary cancers of the central nervous system. The distinction of GBM as “multi-forme” is representative of its exceptional genetic heterogeneity. Extensive gene expression profiling has identified distinct disease groups within the GBM umbrella, and has revealed genetic alterations in several growth factor signaling pathways. In our lab, we are interested in the RTK/RAS/PI3K signaling axis and how the receptor tyrosine kinase (RTK) Epidermal Growth factor Receptor (EGFR) contributes to gliomagenesis.

EGFR is amplified in approximately 50% of primary GBMs and often harbors a deletion from exons 2-7 resulting in its constitutive activation. Expression of this mutant EGFRvIII enhances GBM tumorigenicity, increases invasiveness, and conveys increased chemo- and radio-resistance. Our lab recently reported on the suppression of microRNA 9 (miR-9) specifically by EGFRvIII activity. In this study, we showed that inhibition of miR-9 by EGFRvIII results in a de-repression of its target gene, Forkhead Box Protein 1 (FOXP1). Expression of FOXP1 was found to increase tumorigenicity in vivo and predict poor patient survival in a cohort of 131 GBM patients.

My project will investigate the effect of FOXP1 on GBM oncogenesis. FOXP1 is a motor neuron specific transcription factor widely regarded for its ability to transcriptionally repress gene expression. Using genetically altered glioma cells knocked out for FOXP1, we will perform ChIP-sequencing to identify the DNA binding sites of FOXP1 with the goal of identifying how FOXP1 affects gene expression in GBM. We will perform RNA-sequencing in parallel to determine the downstream signaling pathways involved in FOXP1 DNA binding. Based on these results we will examine how FOXP1 influences the phenotype of GBM. Specifically, we will investigate the effect of FOXP1 expression on some of the hallmarks of GBM such as migration, invasion, proliferation and angiogenesis.

The role of FOXP1 in cancer pathogenesis is unclear. Through this project we hope to gain insight into the role of transcriptional repression in driving the oncogenic potential of GBM.

PUBLICATIONS (resulting from this training)

Trainee recently appointed to grant: publications are still in progress.