Year: 2015
Type: dissertation
Abstract: MYCC over-expression and amplification is a hallmark of the most aggressive subtype of medulloblastoma, yet mechanisms by which Myc drives group 3 medulloblastoma pathogenesis remain unclear. Previously our lab discovered JPO2 as a novel Myc co-transforming protein that acts as a Myc transcriptional co-repressor of the potent tumour suppressor TSP-1. My thesis project investigated the hypothesis that the Myc-JPO2 signalling axis regulates cellular and molecular pathways important in medulloblastoma transformation. My thesis studies have demonstrated that TSP-1 has potent anti-metastatic effects in Myc-induced MB xenograft models, and also mediates chemo- and radio-sensitivity via down-regulation of PI3K signalling in MB cells. Significantly, treatment with pharmacologic TSP-1 peptidomimetic, ABT-898, induces apoptosis in two murine models of Myc-driven group 3 MB. My studies demonstrated that ectopic expression of JPO2 also directly induces formation of metastatic and infiltrative MB phenotype in part by augmenting PI3K/AKT signalling via interaction with LEDGF/p75, a pro-survival and pro-migratory oncoprotein in MB. My aggregate findings identify JPO2 as an important modulator of the pro-metastatic Myc-P13K/AKT signalling pathway in MB and indicate TSP-1 mediated suppression of the Myc-JPO2-PI3K signalling axis as an attractive therapeutic approach to target metastatic MB.
Source: TSpace (University of Toronto)
Author: Tiffany Sin Yu Chan
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2563106115