About the Project
We previously showed that a C-terminal fragment of FGFR1, traffics to the nucleus and regulates the expression of target genes. We confirmed Granzyme B (GrB) as the protease that mediates cleavage and showed that GrB inhibition blocks specific FGF-dependent effects. We demonstrated that this phenomenon also occurs in vivo in invasive breast cancer and have identified a panel of FGFR1-regulated target genes, all of which regulate cell migration likely reflecting an invasive signature (Chioni and Grose 2012). Thus we described a novel mechanism by which FGF signalling can regulate cancer cell behaviour, and suggest a novel therapeutic target for treatment of invasive breast cancer. We showed that endogenous GrB plays a promigratory role, at least in part through cleaving FGFR1.
This proposed project is a natural progression from our previous studies and is based on two key findings regarding FGFR signalling in breast, pancreatic cancer (Coleman, Chioni et al., 2014; Chioni and Grose, 2012) as well as preliminary data on cervical cancer (unpublished data):
(I) FGFR1 translocates to the nucleus upon stimulation with its ligand and this is correlated with metastatic cell behaviours both in 2D cell culture and 3D organotypic culture model, as well as in human patients.
(II) We have identified in breast cancer a novel mechanism that FGFR1 gets cleaved by Granzyme B (GrB) and the C-terminus portion of FGFR1 then translocates to the nucleus and acts as a transcription factor that regulates various target genes (Chioni and Grose, 2012).
Main aims1. Determine the importance of ligand/receptor interaction in FGFR1 nuclear localisation and hence cancer progression.
2. Investigate whether full length FGFR1 is also translocated to the nucleus.
3. Investigate whether FGFR1 kinase activity is required for nuclear FGFR1 localisation and/or target gene regulation.
4. Investigate further the FGFR1 target genes
The potential PhD student will become proficient in a wide range of cellular and molecular techniques (e.g. Western blots, PCR, overexpression of FGFR(s), RNAi, functional studies such as proliferation, migration, invasion, organotypic modelling) that will be used to answer important scientific questions relating to cell signalling and cancer.
Stacey J Coleman, Athina-Myrto Chioni, Mohammed Ghallab, Rhys K Anderson, Nicholas R Lemoine, Richard P Grose, Hemant M Kocher (2014) ‘Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells is necessary for pancreatic cancer cell invasion’ EMBO Molecular Medicine (accepted).
Chioni AM, Grose R (2012) FGFR1 cleavage and nuclear translocation regulates breast cancer cell behaviour. Journal of Cell Biology. 197(6):801-17
Chioni A-M, Grose R. (2008). Organotypic modelling as a means of investigating epithelial-stromal interactions during tumourigenesis. Fibrogenesis & Tissue Repair. 1:8
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