Functional heterogeneity of FGF receptors in glioblastoma cancer stem cells
About the project
A 3 year fully funded PhD studentship is available in the Astroglia Cell Biology Group at Cardiff University’s European Cancer Stem Cell Research Institute.
Glioblastoma (GBM) is the most frequent and most lethal type of brain cancer in adults, with a median survival of only 15-18 months. The poor prognosis of GBM is linked to cancer stem cells that can evade therapy and initiate tumour regrowth. GBM cell plasticity – the ability to adopt stem-like states that permit cancer cell self-renewal and therapy evasion – is affected by multiple cell-autonomous and non-cell-autonomous factors. Better understanding of the molecular mechanisms that govern GBM cell plasticity may lead to new and better treatments that can delay or prevent tumour recurrence.
We have previously demonstrated a regulatory feedback loop that maintains the identity of GBM stem cells (Jimenez-Pascual et al. Cancer Disc. 2019). As part of this feedback loop, the growth factor FGF2 is released in the extracellular environment and activates FGF receptor 1 (FGFR1) present on the cell surface of GBM stem cells, leading to downstream activation of stem cell transcription factors. Importantly, transcriptional profiling shows that approximately 30% of GBM patient tumours express signatures of FGF2/FGFR1 and stem cell transcription factors. We have further shown that GBM cells express other FGF receptors as well, but their functions remain largely obscure.
In this project, we will dissect the molecular functions of FGF receptors in GBM, particularly in GBM stem cells. We will characterise the expression of FGF receptors across patient tumours and cellular subpopulations using flow cytometry and functional in vitro and in vivo assays (Aim 1). We will use RNA-sequencing and other OMICs approaches to investigate mechanisms of cell plasticity in GBM cell populations expressing specific FGF receptors (Aim 2). CRISPR targeting of FGF receptors and candidate downstream effectors will validate their functions in GBM cell plasticity (Aim 3).