Dr J Howard Pringle
Reader in Molecular Pathology
Tel: 0116 252 3227
Fax: 0116 2523274
Office: Room 340, Robert Kilpatrick Clinical Sciences Building, University of Leicester, Leicester Royal Infirmary, Leicester LE2 7LX
- PhD Warwick
- BSc (CNAA), Bristol
The main emphasis of my current research is to investigate the molecular and cellular mechanisms that influence the development of cancer and effect the progression of this disease. Identifying these molecular alterations that distinguish cancer cells from normal cells is currently a major priority for cancer research as these events can be used to recognize individuals at risk of this disease and predict the pathological behaviour of the developing tumour. These molecular changes may also indicate which therapy is likely to be successful for a specific tumour. Therefore the main challenge in successful cancer treatment and prevention is the detection of early lesions that have the potential to progress. My current approach is to investigate genetic variation, genome instability, somatic mutations and promoter methylation using DNA and RNA extracted from tumour biopsies representing different stages of tumour development. These genetic and epigenetic events are then correlated with changes in cell phenotype by gene expression studies and immunohistochemistry.
I am currently using genomic methods to profile these events with techniques such as array-CGH, gene expression arrays and micro-RNA expression arrays. My experience of working in the old Department of Pathology has provided expertise in DNA and RNA extraction from tissues including the use of tissue micro-dissection to ensure the cellular source of these molecules. The histopathology tissue archives at the University Hospitals of Leicester (UHL) represent a significant resource of tumour tissue but appropriate methods are required for the extraction and analysis of nucleic acids from these formalin fixed embedded tissues.
The genomic profiles from these tissues are then used to identify candidate genes and pathways in these tissues. Bioinformatics and statistical analysis of these data will define genes with potentially important roles in tumour genesis and useful surrogate markers predictive of later clinical disease. The aim is to validate these genes and determine their predictive value as markers of risk, diagnosis or prognosis. This approach also extends to detection of these molecular changes in serum or plasma DNA or RNA which could be used to screen the population. Circulating DNA and RNA extracted from blood has been shown to be derived from the cancer cells. It is also important to determine the molecular and cellular mechanisms by which these genetic events influence the development and progression of cancer. Therefore novel genes and pathways could be further analysed in model experiments by collaboration with other research groups.
To facilitate this research I am collaborating with clinical research groups ensuring that tissue and blood is obtain locally for melanoma, breast cancer, lung cancer and colorectal cancer (CRC).
The focus of the skin cancer group is to study genetic and cellular mechanisms influencing the development and progression of melanoma. This group comprises Dr Peter Hutchinson (Consultant Clinical Dermatologist, UHL), Dr Joy Osborne (Clinical Dermatologist, UHL), Dr Gerald Saldanha (Senior Lecturer and Consultant Histopathologist), and Dr Mark Bamford (Consultant Histopathologist, UHL). We have previously published several studies into BRAF, NRAS and HRAS mutation frequencies in cutaneous melanoma and other melanocytic tumour types. We are now in a position to expand this work to screen other genetic aberrations and biomarkers in melanoma which can be diagnostic or prognostic for this disease. For example, in collaboration with Dr Eugene Tulchinsky (Senior Lecturer) we are investigating the role of the master regulators of epithelial to mesenchymal transition (MR-EMT) to melanoma progression, stemness and drug resistance.
The breast group is also interested in early events influencing the development and progression of breast cancer. This group comprises Professor Louise Jones (Consultant Histopathologist, Barts and The London, CRUK) and Dr Jacqui Shaw (Senior Lecturer). We have shown that specific isoforms of the matrix protein tenascin-C with selected type III fibronectin repeats domain B (exon 14) and domain D (exon 16) are expressed in invasive and pre-invasive breast cancer. The purpose of this work is to analyse in detail the mechanisms by which these proteins mediate their different effects on tumour cell proliferation, migration and invasion. In particular how specific isoforms with alternatively spliced exon 14 and additional domain 1(AD1) promote invasion. This work aims to develop novel therapies to prevent early invasion and metastasis in this disease.
In colorectal cancer (CRC) my collaborators include:- Mr John Jameson (Colorectal Surgeon UHL), Prof. J Jankowski (Consultant Gastroenterologist, UHL ,Histopathology Unit Cancer Research UK, London Research Institute, London, United Kingdom), Dr K West (Consultant Histopathologist UHL). Mr Imran Aslam (Clinical Research Fellow). We have shown the importance of ectopic expression of P-cadherin which correlates with promoter hypomethylation and enhanced intestinal crypt fission early in colorectal carcinogenesis. Currently we have two projects investigating similar early markers of cancer. The first will identify blood associated micro-RNAs (miRs) as novel non-invasive biomarkers for detection of tumours and this project aims to investigate the potential of specific miRs for diagnosis, progression and prognosis tests.
Photomicrograph of colorectal tissue showing differential expression of miR-21 between normal mucosa (top left) and adenocarcinoma (right) by in situ hybridisation using locked olilgonucleotide probes labelled with digoxigenin. This miR is upregulated in colrectal cancer and is an important biomarker of progression, prognosis, and response to therapy.
To view Dr Pringle's publications, please use the link below: