We are interested in how cancer cells interact with each other and the microenvironment. We investigate how cancer cells develop resistance to therapies and design drug combination approaches to overcome this.
PHLDA1 mediates drug resistance in receptor tyrosine kinase driven cancer. Cell Reports (2018) 22:1-13. PMID: 29490281
Pancreatic cancer cell invasion is mediated by nuclear translocation of FGFR1 and FGF2 in stellate cells. EMBO Mol Med (2014) 6:467-481. PMID: 24503018
FGFR1 cleavage and nuclear translocation regulates breast cancer cell behavior. Journal of Cell Biology. (2012) 197(6):801-17. PMID: 22665522
The role of fibroblast growth factor receptor 2b in skin homeostasis and cancer development. EMBO Journal (2007) 26(5):1268-78. PMID: 17304214
Receptor Tyrosine Kinase (RTK) signalling can be a positive driving force for cell proliferation, survival and migration but it is kept under tight control via feedback loops. In cancer, these controls can be bypassed by a variety of mechanisms and we are investigating how this happens.
We focus on breast, pancreatic and endometrial cancer, using 2-D and 3-D cell-based models to investigate how cellular behaviour changes when RTK signalling is altered. We collaborate with clinical colleagues to determine the translational significance of our findings through analysis of patient samples.
Our current research aims:
1. Targeting oncogene addiction and drug resistance
Fibroblast Growth Factor Receptor (FGFR) mutations are key drivers of up to 20% of endometrial cancer and a number of cancers show dependency on oncogenic FGFR signaling, making FGFRs attractive targets for targeted therapies. We have used phosphoproteomics and gene expression analysis to dissect resistance pathways that are established in drug resistant cancer cells, to develop novel combination therapy approaches.
We have recently identified a new resistance pathway, mediated by PHLDA1 dependent regulation of Akt signalling, with implications for targeted therapies against both FGFRs and HER2. In an exciting new project, we are now adopting similar approaches to identify drug resistance mechanisms in glioblastoma.
2. Modelling breast cancer development in 3D culture
3D modelling fulfils a critical role in research, allowing for complex cell behaviour and interactions to be studied in physiomimetic conditions. We have used the Breast Cancer Now Tissue Bank, an invaluable resource of primary cells isolated directly from patients, to interrogate the interactions between myoepithelial and luminal cells in 3D using collagen gels.
Using lentiviral transduction of isolated cells, we have developed a model that allows us to study early events in breast cancer development, to help understand how breast cancer progresses, with the ultimate aim of improving early diagnosis and treatment.
3. Nuclear trafficking of FGFRs
We have discovered that, rather than signalling from the cell surface or within endosomes, FGFRs can be proteolytically cleaved following activation and that the cytoplasmic portion of the receptor can traffic to the nucleus and regulate gene transcription. We have identified this behaviour in invasive breast cancer cells both in vitro and in vivo.
Our goals are to dissect the mechanisms controlling proteolytic cleavage and trafficking and to identify the full range of target genes and identify novel putative targets to block the pro-invasive effects of nuclear FGFR signalling. We have shown that nuclear FGFR signalling is a critical mediator of cancer-stroma cross-talk in pancreatic cancer, and we are exploring the therapeutic potential of FGFR inhibition in blocking pancreatic cancer progression.
Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway Wilcz-Villega E, Carter E, Ironside A et al. EMBO Molecular Medicine (2020) 12(7)
Pancreatic Cancer Organotypic Models. Coetzee A, Grose R, Kocher H Curr Top Microbiol Immunol (2019) (2)
Emerging Roles of Fibroblast Growth Factor 10 in Cancer. Clayton NS, Grose RP Front Genet (2018) 9(1) 499-499
PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer Fearon AE, Carter EP, Clayton NS et al. Cell Reports (2018) 22(7) 2469-2481
Fibroblast growth factor-mediated crosstalk in cancer etiology and treatment. Clayton NS, Wilson AS, Laurent EP et al. Dev Dyn (2017) 246(1) 493-501
A 3D in vitro model of the human breast duct: A method to unravel myoepithelial-luminal interactions in the progression of breast cancer Carter EP, Gopsill JA, Gomm JJ et al. Breast Cancer Research (2017) 19(7)
3D Organotypic Culture Model to Study Components of ERK Signaling. Chioni A-M, Bajwa RT, Grose R Methods Mol Biol (2017) 1487(1) 255-267
A 3D in vitro model of the human breast duct: unravelling myoepithelial-luminal interactions in breast cancer Carter E, Gomm JJ, Jones LJ et al. Breast Cancer Research and Treatment (2016) 159(1) 187-188
Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma. Carapuça EF, Gemenetzidis E, Feig C et al. Journal of Pathology (2016) 239(1) 286-296
Reduced expression of histone methyltransferases KMT2C and KMT2D correlates with improved outcome in pancreatic ductal adenocarcinoma GROSE RP, Dawkins JBN, Wang J et al. Cancer Research (2016) (1)
Dr Edward Carter, Dr Lucía Rodríguez Fernández, Dr Chris Milton
Ms Yasmine Tanner, Ms Abigail Wilson, Demi Wiskerke