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

• Main Author: Jimenez-Pascual, Ana
• Format: Dissertation
• Language: English
• Published: Cardiff University 2019

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.