Research projects

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FGF signalling in regulation of tumour immune microenvironment

Supervisor: Dr Tomoko Iwata

Research areas: tumour immune microenvironment, growth factor signalling, molecular pathology

Project outline: Immune “cold” tumours are tumours with little infiltrations of T lymphocytes and therefore immune suppressed, developed by a mechanism of evasion from immune surveillance through cancer progression (Hallmarks of Cancer). They pose a challenge for therapy options, particularly for checkpoint inhibitors, which are otherwise promising in many cancer types. Bladder cancer is common, and one of the most highly mutated cancers, similar to lung cancer and melanoma.

While potentially a preferred target of immunotherapy, the response is still limited. Recent molecular classification of muscle-invasive bladder cancer showed that FGFR3 overexpression was frequently observed in luminal-papillary subtype and non-T cell inflamed, immune cold tumours. Studies in our lab showed that activatinf FGFR3 mutation, frequently identified in bladder cancer, suppresses anti-tumour inflammation in the early stage of bladder tumour pathogenesis, thereby increasing overall frequency of tumorigenesis (1, 2). However, the mechanism of immune-suppression by FGFR3 in immune-cold subtype of bladder cancer is still unclear.

Myeloid cells, such as macrophages and neutrophils, could play anti- or pro-tumour roles depending on the stages of tumour progression. We hypothesized that sequence of signalling from myeloid cells to T cells may lead to overall immune suppression of the tumour. While suppression of anti-tumour inflammation may increase tumorigenesis, suppression of pro-tumour neutrophils may allow re-population of T cells in the tumour thereby sensitising tumours to immune checkpoint therapy. Suppression of neutrophils may also inhibit metastasis.

Clinically, FGFR3 is one of the most important therapeutic targets in bladder cancer, and many drugs that target FGF signalling in cancers are already available (3). Therefore, a better understanding of the role of FGF signalling, and that of FGFR3, in regulation of tumour immune microenvironment will provide better opportunities for translation in bladder cancer and others.

Project aims: In this project, the student will investigate the spatial relationship of FGF signalling and myeloid cells in the tumour immune microenvironment in tumour tissues, and evaluate the potentials of targeting FGF signalling and myeloid cells in improving effectiveness of immunotherapy.

Technique used: The student will have opportunities to be trained in a variety of cutting-edge histopathology techniques and technologies, both lab-based and image analysis, including multispectral image analysis, special and quantitative digital pathology, immune and gene profiling, management of tissue resources of model and clinical specimens.

References

1. Foth M, Ahmad I, van Rhijn BW, van der Kwast T, Bergman AM, King L, et al. Fibroblast growth factor receptor 3 activation plays a causative role in urothelial cancer pathogenesis in cooperation with Pten loss in mice. J Pathol. 2014;233(2):148-58.
2. Foth M, Ismail NFB, Kung JSC, Tomlinson D, Knowles MA, Eriksson P, et al. FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation. J Pathol. 2018;246(3):331-43.
3. Ahmad I, Iwata T, Leung HY. Mechanisms of FGFR-mediated carcinogenesis. Biochim Biophys Acta. 2012;1823(4):850-60.

Contact address

Dr Tomoko Iwata
School of Medicine, Dentistry and Nursing
Medical Genetics and Pathology, Laboratory Medicine
Queen Elizabeth University Hospital
1345 Govan Road, Glasgow G51 4TF

PI web site: Tomoko Iwata

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Neutrophils and Chemokine Signalling in the Tumour Immune Micro-environment and Progression

Supervisor: Dr Tomoko Iwata

Checkpoint inhibitor immunotherapy is promising, however still requires an improvement in response and development of markers to predict the patients who would benefit from this therapy. 

Neutrophils are abundant blood cell population and known to play anti- or pro-tumour roles depending on the context. Expressed in the neutrophils, a chemokine receptor CXCR2 plays an essential role in their recruitment to inflammatory cites, and its inhibition has been shown to suppress tumorigenesis and metastasis in various cancer types. Furthermore, studies in the pancreatic cancer model have shown that Cxcr2 inhibition resulted in a reduction of pro-tumour neutrophils in tumours, allowing T cells to repopulate, thereby sensitizing them to the checkpoint inhibitor. 

In the bladder, an increased expression of CXCR2 ligands is reported to be associated with tumour progression and poor prognosis, however the roles of tumour infiltrating neutrophils remain largely undefined. In order for neutrophils to be targeted in bladder cancer, it is essential to obtain a better understanding of neutrophil biology in the bladder, in comparisons to other tumour types. 

The project asks the following questions: 

• What are the roles of tumour-infiltrating neutrophils in tumour progression in the bladder? 
• What are the characteristics of immune phenotype of neutrophil-enriched tumours, and how do they related to the disease progression? 

We will explore the neutrophil-enriched tumour microenvironment by characterizing the topography of immune cell populations and gene expressions in mouse and human tumour tissues. 

Aims: 

1. to establish methodologies in multiplex immunohistochemistry (mIHC) followed by the quantitative pathology imaging (QPI) and evaluate the validity of artificial intelligence (AI) / machine learning-based analytical processes in digital pathology platforms 
2. to characterise the relationships between tumour infiltrating lymphocytes and Cxcr2+ myeloid cells by topographical analysis 
3. to identify the critical factors leading to the above immune phenotype by gene expression profiling and analysis at the tissue level. 

The overall goal of this study is to understand the roles of neutrophils in bladder cancer progression, and to evaluate the potential of neutrophils or CXCR2 as a new target of immunotherapy. 

Techniques: Through this project, the student is expected to gain a significant expertise in tissue-based research based on hands-on experiences in a variety of cutting-edge histopathology technologies, quantitative digital pathology image analysis, immune and gene profiling, management of tissue resources and large-scale data based on model and clinical specimens. 

References

1. Powles, T., Immune Checkpoint Inhibitors for Urologic Cancer: The Tip of the Iceberg? Eur Urol, 2015. 68(2): p. 280-2. 
2. Coffelt, S.B., M.D. Wellenstein, and K.E. de Visser, Neutrophils in cancer: neutral no more. Nat Rev Cancer, 2016. 16(7): p. 431-46. 
3. Jamieson, T., et al., Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. J Clin Invest, 2012. 122(9): p. 3127-44. 
4. Steele, C.W., et al., CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. Cancer Cell, 2016. 29(6): p. 832-845. 
5. Foth, M., et al., Fibroblast growth factor receptor 3 activation plays a causative role in urothelial cancer pathogenesis in cooperation with Pten loss in mice. J Pathol, 2014. 233(2): p. 148-58. 
6. Foth, M., et al., FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation. J Pathol, 2018. 246(3): p. 331-343. 
7. Gartrell, R.D., et al., Quantitative Analysis of Immune Infiltrates in Primary Melanoma. Cancer Immunol Res, 2018. 6(4): p. 481-493. 

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Overview

Our concept of Molecular Pathology research stems in the tissue-based investigations that provide the important bases for Precision Medicine. Understanding the disease mechanism helps development of new therapies. Therapy stratification could be enhanced by better prediction of therapy response by molecular, and non-invasive, novel biomarkers. The disease area we work on encompasses cancer, inflammation, cardiovascular diseases, and many others. The research projects can address biological questions (basic science) and/or those in alignment with clinical gap of knowledge and diagnostic needs (clinical).

Use of modern technologies by the well-trained, skilled scientists and healthcare practitioners play an important role in delivering Precision Medicine. Our research projects can involve approaches such as:

• histopathology
• multiplex immunofluorescence
• quantitative pathology image analysis
• immune profiling
• digital pathology
• machine learning
• genetics, such as Next Generation exome and genomic sequencing and expression profiling.

Our research groups are located in the University of Glasgow labs within Laboratory Medicine Building, Queen Elisabeth University Hospital campus. Across our clinical and academic staff interests, the opportunities for Molecular Pathology research is offered to both medical and life science students. Our projects benefit from the close working relationship with Glasgow Tissue Research Facility (GTRF) as well as collaborations with the Schools in the College of Medical, Veterinary and Life Sciences.

Our PhD programmes offer training in tissue-based research using modern technologies in the forefront of Molecular Pathology. The project could address important biological questions or clinical needs and may involve use of model and/or clinical specimens, as well as images, numerical and clinical data. Supervisors are clinical and/or non-clinical academics in UofG and NHS, in close collaboration with research institutes and schools of UofG, such as Institute of Cancer Sciences, Infection, Immunity and Inflammation, and Cardiovascular and Medical Sciences.

Study options

PhD

• Duration: 3/4 years full-time; 5 years part-time

Individual research projects are tailored around the expertise of principal investigators.