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Microenvironmental FGF2 regulates glioblastoma stem cells through FGFR1- ERK1/2-ZEB1 axis

Jimenez-Pascual, Ana 2019. Microenvironmental FGF2 regulates glioblastoma stem cells through FGFR1- ERK1/2-ZEB1 axis. PhD Thesis, Cardiff University.
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Abstract

Glioblastoma (GBM) is the most lethal and aggressive brain cancer in adults with a median survival of approximately 20 months after diagnosis. GBM represents a highly infiltrative and heterogenous tumour, formed by populations of cells harbouring diverse molecular signatures and responses to therapy. Tumour recurrence and poor prognosis have been thought to be a consequence of resident glioblastoma stem cells (GSCs), which are quiescent cells capable of self-renewal, migration and initiation of new tumours. These cells are subject to cell-autonomous factors and extrinsic cues, which are translated into cell responses that promote tumour progression. Particularly, trophic factors from the tumour microenvironment, such as fibroblast growth factor 2 (FGF2), are essential to GBM growth and GSC maintenance. FGF2 and its cognate receptors have been linked to malignancy and progression in GBM as they promote angiogenesis, proliferation and GSC self-renewal. However, the specific mechanisms of how this growth factor contributes to GSC functions remain incompletely understood. Therefore, we analysed expression of FGF receptors (FGFRs) and the effects of FGF2 on patient-derived glioblastoma cells. We found that FGF2 induces expression of the stemness-associated transcription factors ZEB1, SOX2 and OLIG2. Analysis of FGFR1-3 function using knockdown approaches in patient-derived glioblastoma cell lines revealed that FGFR1 was the only FGFR relevant for GSC maintenance. FGFR1 knockdown reduced sphere/colony-formation, invasion and increased survival in xenograft mouse models. On the other hand, serial dilution orthotopic xenografts of FGFR1+ sorted cells revealed higher tumour formation capacity than FGFR1- cells, consistent with a stem cell population. We found that differentiated cancer cells showed a reduction in FGFR1, ZEB1, SOX2 and OLIG2 expression, and that FGFR1 regulated ZEB1 function through ERK1/2 signalling. Finally, analysis of large-scale gene-expression datasets revealed association of FGFR1 with the mesenchymal subclass of glioblastoma and increased expression levels of FGFR1 in 30-40% of cases. Therefore, in this thesis we demonstrate that FGF2-FGFR1 axis regulates key stemness transcription factors and identify FGFR1 as a potential GSC marker and therapeutic target.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Funders: Tenovus Cancer Care
Date of First Compliant Deposit: 25 October 2019
Last Modified: 07 Jan 2022 02:33
URI: https://orca.cardiff.ac.uk/id/eprint/126303

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