Professor Stewart Fleming

Professor of Cellular and Molecular Pathology

Understanding the genetics initiating and driving progression of kidney cancer

Address:

University of Dundee
Ninewells Hospital and Medical School
Dundee
DD1 9SY

Phone Number:

+(44) 01382 496488

Email Address:

s.fleming@dundee.ac.uk

Biography

Stewart Fleming graduated in Immunology (1978) and Medicine (1980) from the University of Glasgow.  After junior hospital training posts in Glasgow he moved to a Clinical Lectureship in Pathology in the University of Southampton.  While here he completed his thesis on the Cellular Differentiation in Renal Carcinoma which was awarded MD with Honours from the University of Glasgow (1988).  He was gained Membership of the Royal College of Pathologists in 1987 and Fellowship (FRCPath) in 1997. He was awarded the Oakley Lecture of the Pathological Society of Great Britain and Ireland in 1991.  He moved to Senior Lecturer then Reader in Pathology at the University of Edinburgh in 1988 until 2000. He was appointed to the Chair of Cellular and Molecular Pathology in the University of Dundee in 2001and Honorary Consultant Pathologist to NHS Tayside.  He has been the Scottish Chairman and Executive Member of the Royal College of Pathologists, chair of the Research Committee of the Pathological Society and a member of both the WHO and International Society of Urological Pathologists committees for Renal cancer classification.  He has recently been elected as Chairman of the British Association of Urological Pathologists.  He has published over 130 peer reviewed articles, several textbook chapters and has edited Muir’s Textbook of Pathology (14th Edition).

He has an extensive UK wide consultation practice for the diagnosis of renal tumours and is the consultant renal and transplant pathologist for NHS Tayside and NHS Fife.

Research

Renal cancer is amongst the commonest malignancies affecting 6,500 new patients per year in the UK.  It is associated with a high mortality and limited success of non-surgical treatment. We have engaged in a long term study for the past 20 years identifying several of the genes which are altered in renal cell carcinoma (RCC), the commonest form of malignancy in adults and Wilms’ tumour the childhood form of the disease. Several years ago we found that RCC is caused by mutations in one of several genes which control the hypoxia signalling pathway particularly the Von Hippel Lindau gene.

Our recent work has shown rather surprisingly that mutations in the nuclear encoded genes fumarate hydratase and succinate dehydrogenase B are found in subsets of RCC.  We have established the diagnostic criteria for the identification of these tumours and laboratory testing to analyse the types of mutational events further. We are currently engaged in identifying the mechanisms involved in SDHB induced tumourigenesis.

One of the strongest risk factors for the development of RCC is high blood pressure.  We are researching the mechanisms behind this observation. In particular we are interested in the role of the renin angiotensin aldosterone system in driving renal epithelial proliferation.

Publications

Fleming S., Mayer NJ., Vlatkovic LJ., McLean J., McConachie M., Baty D. Signalling pathways in succinate dehydrogenase B associated renal carcinoma. Histopathology  2013 Aug 12. doi: 10.1111/his.12250. [Epub ahead of print]

Srigley, J. et ISUP.  The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia.  American Journal of Surgical Pathology, 2013, 37;1469–1489

Delahunt, B. et ISUP. The International Society of Urological Pathology (ISUP) Grading System for Renal Cell Carcinoma and Other Prognostic Parameters. American Journal of Surgical Pathology. 2013, 37; 1490–1504

Tan, P. H. et ISUP. Renal Tumors: Diagnostic and Prognostic Biomarkers. American Journal of Surgical Pathology., 2013,37; 1518–1531

Trpkov, K. et ISUP. Handling and Staging of Renal Cell Carcinoma: The International Society of Urological Pathology Consensus (ISUP) Conference Recommendations. American Journal of Surgical Pathology, 2013, 37; 1505–1517

Buckley, C., Nelson, R., Sharp, M., Fleming, S., Kenyon, C., Mullins, L., Steppan, D. & Mullins, J. Complementation of juxtaglomerular cell granulation in Ren- 1d null mice by human renin FASEB J, 2013 27:1165.20

Sandilands, A., Smith, F. J. D., Lunny, D. P., Campbell, L. E., Davidson, K. M., MacCallum, S. F., Corden, L. D., Christie, L., Fleming, S., Lane, E. B. & McLean, W. H. I. Generation and characterisation of keratin 7 (K7) knockout mice PLoS ONE. 8, 5, 11 p., e6440

Bambury RM, Battley JE, McCarthy A, Brady C, O'Reilly S, Kelly PJ, O'Brien F, Sweeney P, Fleming S, Mayer NJ, Power DG. Translocation Renal Cell Carcinomas: An Evolving Entity and a Member of the Microphthalmia Transcription Factor-Associated Family of Tumors.  Clin Genitourin Cancer. 2013 11(3):357-61

Appleyard MV, Murray KE, Coates PJ, Wullschleger S, Bray SE, Kernohan NM, Fleming S, Alessi DR, Thompson AM. Phenformin as prophylaxis and therapy in breast cancer xenografts. Br J Cancer. 2012;106(6):1117-22

Berenjeno IM, Guillermet-Guibert J, Pearce W, Gray A, Fleming S, Vanhaesebroeck B. Both p110a and p110b isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor. Biochem J. 2012, 442 :  151-159

García-Martínez JM, Wullschleger S, Preston G, Guichard S, Fleming S, Alessi DR, Duce SL. Effect of PI3K- and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice.  Br J Cancer. 2011;104(7):1116-25

Tummala H, Fleming S, Hocking PM.; The D153del Mutation in GNB3 Gene Causes Tissue Specific Signalling Patterns and an Abnormal Renal Morphology in Rge Chickens. PLOS ONE 2011 6;8 Article Number: e21156   DOI: 10.1371/journal.pone.0021156

Gill AJ, Pachter NS, Chou A, Young B, Clarkson A, Tucker KM, Winship IM, Earls P, Benn DE, Robinson BG, Fleming S, Clifton-Bligh RJ. Renal Tumors Associated With Germline SDHB Mutation Show Distinctive Morphology. American Journal of Surgical Pathology   2011 35;1578-1585

Miller G, Matthews S, Reinheckel T, Fleming S; Watts C. Asparagine endopeptidase is required for normal kidney physiology and homeostasis. FASEB Journal  2011 25: 1606-1617

Wullschleger S, Sakamoto K, Johnstone L, Duce S, Fleming S, Alessi DR. How moderate changes in Akt T-loop phosphorylation impact on tumorigenesis and insulin resistance. Dis Model Mech. 2011 Jan;4(1):95-103.

Fleming S. Renal cell carcinoma in acquired cystic kidney disease. Histopathology. 2010 ;56(3):395-400

Rafiqi FH, Zuber AM, Glover M, Richardson C, Fleming S, Jovanović S, Jovanović A, O'Shaughnessy KM, Alessi DR. Role of the WNK-activated SPAK kinase in regulating blood pressure. EMBO Mol Med. 2010, 2; 63-75

Housley SL, Lindsay RS, Young B, McConachie M, Mechan D, Baty D, Christie L, Rahilly M, Qureshi K, Fleming S. Renal carcinoma with giant mitochondria associated with germ-line mutation and somatic loss of the succinate dehydrogenase B gene. Histopathology. 2010 ;56(3):405-8.

Nobrega MA, Solberg Woods LC, Fleming S, Jacob HJ. (2009) Distinct genetic regulation of the progression of diabetes and renal disease in the Goto-Kakizaki (GK) rat. Physiol Genomics. 2009 ;39(1):38-46

Liu X, Bellamy CO, Bailey MA, Mullins LJ, Dunbar DR, Kenyon CJ, Brooker G, Kantachuvesiri S, Maratou K, Ashek A, Clark AF, Fleming S, Mullins JJ. (2009) Angiotensin-converting enzyme is a modifier of hypertensive end organ damage. J Biol Chem. 2009 Jun 5;284(23):15564-72.

McQuarrie EP, Mackinnon B, Young B, Yeoman L, Stewart G, Fleming S, Robertson S, Simpson K, Fox J, Geddes CC; Scottish Renal Biopsy Registry (2009) Centre variation in incidence, indication and diagnosis of adult native renal biopsy in Scotland. Nephrol Dial Transplant. 2009 May;24(5):1524-8.

Hadad SM, Baker L, Quinlan PR, Robertson KE, Bray SE, Thomson G, Kellock D, Jordan LB, Purdie CA, Hardie DG, Fleming S, Thompson AM. Histological evaluation of AMPK signalling in primary breast cancer. BMC Cancer. 2009;9:307.

Clark EL, Coulson A, Dalgliesh C, Rajan P, Nicol SM, Fleming S, Heer R, Gaughan L, Leung HY, Elliott DJ, Fuller-Pace FV, Robson CN. (2008)  The RNA helicase p68 is a novel androgen receptor coactivator involved in splicing and is overexpressed in prostate cancer. Cancer Res. 2008 Oct 1;68(19):7938-46

Hadad SM, Fleming S, Thompson AM. Targeting AMPK: a new therapeutic opportunity in breast cancer. Crit Rev Oncol Hematol. 2008 Jul;67(1):1-7

Huang X, Wullschleger S, Shapiro N, McGuire VA, Sakamoto K, Woods YL, McBurnie W, Fleming S, Alessi DR (2008) Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J. 2008 Jun 1;412(2):211-21

Heath E, Tahri D, Andermarcher E, Schofield P, Fleming S, Boulter CA (2008) Abnormal skeletal and cardiac development, cardiomyopathy, muscle atrophy and cataracts in mice with a targeted disruption of the Nov (Ccn3) gene. BMC Dev Biol. 20;8:18

Patek CE, Brownstein DG, Fleming S, Wroe C, Rose L, Webb A, Berry RL, Devenney PS, Walker M, Maddocks OD, Lawrence NJ, Harrison DJ, Wood KM, Miles CG, Hooper ML. (2008) Effects on kidney disease, fertility and development in mice inheriting a protein-truncating Denys-Drash syndrome allele (Wt1tmT396). Transgenic Res. 17(3):459-75.

J. Ross, I. R. Whittle, S. Fleming, K. M. Kurian (2007) Cerebral metastasis of peripheral primitive neuroectodermal tumour (pPNET) - use of cytogenetic abnormalities in diagnosis.  Neuropathology and Applied Neurobiology 33 (4), 471–474.

Bayascos J, Leslie NR, Parsons R, Fleming S, Alessi DR (2005)  Hypomorphic mutation of PDK1 suppresses tumourigenesis in PTEN (+/-) mice. Current Biology 15;1839-1846.

Alam,N.A., Rowan, A.J., Wortham ,N.C., Pollard,P.J., Mitchell,M., Tyrer,J.P., Barclay,E., Calonje,E., Manek,S., Adams,S.J. et al. 2003. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum.Mol.Genet.  12:1241-1252.

Teaching

Professor Fleming is the course leader on the Mechanisms of Disease module of the Principles of Health and Disease course for 1st year MB ChB.  He runs a full module in the Life Science Honours 4th year on Neuropathology which is taken by BMSc and BSc student in Neuroscience and Neuroanatomy. He also supervises Honours projects on these courses and runs three SSCs for medical students on Clinical Pathology and Cancer.

He teaches on most of the MB ChB phase 2 systems courses and on the BDS 2 course on Pathology for Dentists.

He is currently an external examiner for MB ChB BAO courses in University College Dublin.

He is a postgraduate clinical academic training advisor in Pathology.

PhD Supervision

Current - Mr Ismail El-Mokadem CHROMOSOME 9 ALTERATIONS IN RENAL CARCINOMA

Dr Lesley Christie CLONALITY IN LANGERHANS CELL HISTIOCYTOSIS awarded MD in 2012 by University of Dundee

Dr Mary Gallacher THE ONCOGENEIC ACTIONS OF WT1 awarded PhD in 2012 by University of Dundee

Dr Sirwan Hadad (Second supervisor) THE ROLE OF AMPKINASE IN BREAST CANCER awarded PhD in 2010 University of Dundee

Dr Sharon King  KiRAS IS A MINERALOCORTICOID RESPONSIVE GENE IN RENAL CELL CARCINOMA awarded PhD in 2009 by University of Dundee

Dr Sharon White (Second supervisor) PATHOLOGY AND GENETICS OF KINDLER SYNDROME PhD awarded 2008 by University of Dundee

Dr Tara Collidge (Second supervisor) SUSCEPTIBILITY GENES IN MALIGNANT HYPERTENSION awarded MD in 2004 by University of Edinburgh

Dr C Whitworth (Second Supervisor) TRANSGENIC MODELLING OF MALIGNANT PHASE HYPERTENSION awarded MD by University of Edinburgh in 1996.

Ms Kathy Williamson DEVELOPMENTAL BIOLOGY OF THE WILMS' TUMOUR GENE awarded PhD by the University of Edinburgh in 1996.

Dr M Rahilly CELL SUBSTRATUM ADHESION AND PROGRESSION OF NEOPLASIA awarded MD by the National University of Ireland in 1995.

Dr K Pritchard-Jones (University Supervisor) INVOLVEMENT OF THE WILMS' TUMOUR GENE (WT1) IN NORMAL DEVELOPMENT AND TUMOURIGENESIS awarded PhD by CNAA in 1992.

Dr M I Nasser IMMUNOHISTOCHEMICAL STUDIES OF CLOTTING FACTORS IN RENAL DISEASE awarded by the University of Southampton in 1987.