Research

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.

For more information, please visit www.groselab.com

Other Activities

• Research Scholarship Programme Review Panel Member - Irish Cancer Society
• Independent Scientific Advisory Panel member - Bone Cancer Research Trust
• Chair for 2016 Gordon Research Conference on Fibroblast Growth Factors in Development & Disease
• STEMnet Ambassador
• Honorary Professor - Wenzhou University, China
• Breast Cancer Now grants committee
• British Association for Cancer Research executive committee

Major Funding

• 2019-2023- Cancer Research UK, Myoepithelial degradome in the progression of DCIS to invasive breast cancer, £473,002
• 2018-2020- Breast Cancer Now, Myoepithelial/luminal cross-talk in the progression of DCIS to invasive breast cancer, £201,816.00
• 2009-2010- Medical Research Council, Tumour suppressive function of Fgfr2b, £343,676.00

Recent Publications

Centrosome amplification mediates small extracellular vesicle secretion via lysosome disruption Adams SD, Csere J, D'angelo G et al. Current Biology (2021) 31(7) 1403-1416.e7

Dissecting FGF Signalling to Target Cellular Crosstalk in Pancreatic Cancer Carter EP, Coetzee AS, Tomas Bort E et al. Cells (2021) 10(7)

Expression of programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand (PD-L1) in adenocarcinomas of the gastroesophageal junction change significantly after neoadjuvant treatment Jomrich G, Kollmann D, Ramazanova D et al. European Journal of Surgical Oncology (2021) (7)

Hallmarks of cancer—the new testament Senga SS, Grose RP Open Biology (2021) 11(7)

Pancreatic Cancer Organotypic Models Coetzee A, Grose R, Kocher H (2021) 430(7) 183-198

Programmed death ligand 2 expression plays a limited role in adenocarcinomas of the gastroesophageal junction after preoperative chemotherapy Jomrich G, Kollmann D, Wilfing L et al. European Surgery - Acta Chirurgica Austriaca (2021) (7)

Tumour microenvironment 3D-modelling: simplicity to complexity and back again Carter EP, Roozitalab R, Gibson SV et al. Trends in Cancer (2021) (7)

Targeting FGFR signalling to disrupt cellular cross-talk in pancreatic cancer Coetzee AS, Carter EP, Milton CI et al. Pancreatology (2020) 20(1) e19-e19

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)

Abstract 5170: Targeting FGFR signaling to disrupt cellular cross-talk in pancreatic cancer Coetzee A, Carter E, Heward J et al. (2019) (10) 5170-5170

Team

Postdoctoral Researchers
Dr Edward Carter, Dr Lucía Rodríguez Fernández, Dr Chris Milton

PhD Students
Ms Yasmine Tanner, Ms Abigail Wilson, Demi Wiskerke

Biography

• 1990-91: Research assistant at Amersham. Developing ELISAs for HIV testing
• 1991-94: BSc in Zoology (University of Bristol)
• 1994-95: Research Associate at Pfizer Central Research. Molecular Sciences Department
• 1995-99: PhD (University College London). Molecular basis of embryonic wound repair (Prof Paul Martin)
• 1999-2001: Postdoctoral researcher (ETH Zurich). Genetically modified mouse models of wound healing (Prof Sabine Werner)
• 2001-2004: Postdoctoral Fellow (CR-UK LRI). FGF signalling in cancer (Dr Clive Dickson)
• 2004-present: Group leader at Barts Cancer Institute