Growth factors are used during development to convey messages that tell cells to divide, survive, migrate, and adopt a particular fate. This is particularly true of the Fibroblast growth factors (FGFs), whose signals are critical for the development of many organs. Since FGFs provide powerful growth signals, their signalling pathway is tightly regulated. However, some cancer cells hijack this pathway to gain a growth advantage over normal cells. FGFs and their receptors, FGFR1 and FGFR2, have been implicated in cancer susceptibility and progression (i.e., breast, cervical, endometrial, prostate, lung cancer), suggesting that FGF signalling may be co-opted by cancer cells. FGFRs signal from the cell membrane and from endosomal compartments via MAPK, PI3K, PLC-gamma and STATs. However, there is evidence that other tyrosine kinase receptors as well as full-length FGFRs, and FGFR1 in particular, can be targeted to the nucleus.
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 (Chioni and Grose 2012). Furthermore, we have shown an association between FGFR signalling and cervical cancer progression (Mahmood et al, 2021). We have demonstrated that FGFR1 and 2 localized to the nucleus of three cervical cancer cell lines (SiHa, HeLa and CaSki), supporting that nuclear FGFRs could act as transcription factors also in cervical cancer. Importantly, 2D and 3D cell cultures demonstrated that FGFR activation can facilitate cell functions correlated with invasive disease (Mahmood et al, 2021).
This proposed project is a natural progression from our previous studies, and it is based on two key findings regarding FGFR signalling in breast, pancreatic and cervical cancer (Coleman, Chioni et al., 2014; Chioni and Grose, 2012; Mahmood et al 2021):
(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).
- Determine the importance of ligand/receptor interaction in FGFR1 nuclear localisation and hence cancer progression.
- Investigate whether full length FGFR1 is also translocated to the nucleus.
- Investigate whether FGFR1 kinase activity is required for nuclear FGFR1 localisation and/or target gene regulation.
- Investigate further the FGFR1 target genes