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Institute of Dentistry - Barts and The London

Professor Ken Parkinson , BSc (Hons), PhD

Ken

Professor of Head & Neck Cancer

Email: e.k.parkinson@qmul.ac.uk
Telephone: 0207 882 7185
Room Number: G81, Blizard Building, Institute of Dentistry

Profile

 

During my PhD work in Professor Adam Curtis’ Department of Cell Biology at the University of Glasgow, I developed an interest in epithelial cell biology and quickly realised that understanding neoplastic transformation in this cell class was key to understanding most human cancers.After completing my PhD in epithelial cell behaviour, I moved to Birmingham to continue my interest in epithelial cells and develop research interests in cancer.

During this time I developed an international reputation in keratinocyte cell biology that were based around the use and modification of the Rheinwald and Green feeder layer technique. We performed experiments with this system to formulate a hypothesis to explain epidermal skin tumour promotion (Parkinson et al 1982; 1983;1984 reviewed in Parkinson 1985). We proposed, contrary to the general belief at the time, that tumour promoters acted on the normal keratinocytes and caused these cells to die whilst sparing the initiated ones, which then expanded into the space that was left.

Based on work with fibroblasts virtually all other groups at the time were pursuing the idea that tumour promoters were mitogens. Our hypothesis was supported by the concurrent and later work of other groups (Balmain et al Nature1983;1984, Yuspa et al Nature 1985) and is now broadly believed to be correct and at least part of the explanation for tumour promotion.

In Birmingham I developed an interest in keratinocyte stem cells and moved to the Paterson Institute in Manchester where I learnt much about this topic from Chris Potten and Michael Dexter.

In 1988 I moved to the Beatson where I developed an interest in cellular immortalistion and telomeres and in 1994 I was awarded a non time-limited appointment by CR UK (then CRC). It has been during this time that I have established an international reputation in the field of cellular immortalisation, most especially when applied to tumour development and progression. In particular, we were the first group to publish a peer reviewed paper (Loughran et al 1994) linking homozygous deletions of the INK4A locus on chromosome 9p21 to cancer cell immortality (most other groups at the time thought that such deletions were connected with in vitro proliferation). Following up on this we (Loughran et al 1996), concurrently with Gordon Peters and Cathy Reznikoff, showed that the gene responsible was likely to be the tumour suppressor p16INK4A.
All three groups reported an accumulation of p16INK4A upon the serial passage of human cells in vitro but we were the only group to rule out the candidacy of p15INK4B (Loughran et al 1996) and discriminate between the roles of p16INK4A and p14ARF (Munro et al 1999). This work and our parallel work on the role of telomere dysfunction in tumour progression and senescence (Loughran et al 1997; Gordon et al 2003) has led to numerous other publications in top international cancer journals and has been the reason for my invitation to several international meetings on this topic.I presented at the AACR as an invited speaker in the “Educational Session” in front of 2000 delegates in 2002 and was the only UK speaker at the Opinion Leaders meeting in Montego Bay Jamaica in 2004.
This work has formed the basis of recent work that has obtained the first evidence for a role of senescent cells in many age-related diseases and our discovery that p16INK4A is strikingly elevated in cells harbouring integrated HPV (Loughran et al Oncogene 1996) is now part of a diagnostic test for such virally induced cancer of the tonsil.

In 2005 I moved to QMUL in the IOD where I continued my work on the genetics of oral squamous cell carcinoma and cellular senescence forged many collaborations investigating the role of senescent fibroblasts in the tumour environment and developed techniques for enriching and deleting senescent cells from cell populations (Pitiyage et al J. Pathology 2011).
More recently, I have become interested in senescent cell metabolism and have pioneered the analysis of extracellular metabolites produced by senescent cells ( the extracellular senescence metabolome -James et al Journal of Proteome Research 2015) with a view for identifying non-invasive (blood, urine) tests for senescent cells and drugs that delete them (senolytics).
Several of these ESM metabolites are now known to be associated with ageing/longevity, death from cardiovascular diseases, kidney disease and death from all causes and one ESM metabolite citrate may even be causal for type 2 diabetes. Citrate is also an important fuel for some cancer cells and drugs that block citrate import are being developed to treat both type 2 diabetes and cancer. Some of these are currently undergoing clinical trials.

 
Centre: Centre for Oral Immunobiology and Regenerative Medicine

Teaching

 

Postgraudate

MSc Experimental Oral Pathology Seminars Tutorials Practical Thesis examination and project supervision and M.Clin Dent Seminar1

lecture (1 hour)

Undergraduate Teaching

Undergraduate

BDS Year 1 3 lectures

BDS Year 21 lecture

BDS Year 3SSC Tutorials

Research

Research Interests:

 

Senescent cells are known to be important to many age-related diseases and cancer as well as the side effects of cancer therapy and perhaps the poor health of cancer survivors. My current research concentrates of the mechanism by which extracellular citrate (EC) accumulates outside senescent fibroblasts and whether this mechanism can be used as a drug target to slow age-related diseases and cancer.

In collaboration with Professor Inderjeet Dokal we have obtained some evidence that EC accumulates in humans with the diseases Dyskeratosis Congenita where telomeres erode prematurely in humans thus replicating in human subjects what we see in vitro (James et al – manuscript in preparation)

With collaborators in Germany (Dr. Maria Mycielsk and Professor Edward Geissler, University of Renenburg) we are pursuing whether citrate is essential for cancer growth and extending the work on prostate and pancreatic cancer to squamous cell carcinoma of the head & neck with a view to performing clinical trials with drugs that block citrate import.

With collaborators at Imperial College (Drs Jake Bundy and Virag Kiss) we are extending the DKC analysis to other ESM metabolites to assess the mechanism of their accumulation in human subjects.

 

Publications


PRIMARY RESEARCH PUBLICATIONS
CITATIONS 5324
H INDEX 42
RG SCORE 42.18 (ON PUBLICATIONS ALONE)
James, E.L., Lane, J.A.E., Michalek, R.D., Karoly, E.D., Parkinson, E.K. Replicatively senescent human fibroblasts reveal a distinct intracellular metabolic profile with alterations in NAD+ and nicotinamide metabolism. Sci. Rep. (2016) 6:38489. doi: 10.1038/srep38489.
Cirillo, N., Hassona, Y.,Lim, K.P., Celentano, A., Manchella, S., Parkinson, E.K., Prime, S.S. Cancer asscoaited fibroblasts regulate keratinocyte cell-cell adhesion via TGF-β-dependent patwhays in genotype-spcific oral cancer. Carcinogenesis (2017) 38: 76-85.  Epub 2016 Nov 1
.Melling, G.E. , Flannery, S..E ., Abidin, S.A.. , Prajapati P.. , Hinsley E.E. , Hunt S., S.S. , Paterson I.C. , Buttle D.J. ,Lambert D.W. A miRNA-145/TGF-β1 negative feedback loop regulates the cancer-associated fibroblast phenotype Carcinogenesis (2018). 39:798-807. 
James, E.N.L., Bennett, M. Parkinson E.K.The induction of the fibroblast extracellular senescence metabolome is a dynamic process. Sci. Rep. (2018) 8:12148. 
Veeramachaneni R., Walker T., Revil T., De Weck A., Badescu D., O’Sullivan J., Higgins C., Elliott L., Liloglou T., Risk J.M., Shaw R., Hampson L., Hampson, I, Dearden S., Woodwards R., Prime S., Hunter, K. Parkinson, E.K., Ragoussis J., Nalin Thakker, N.Analysis of head and neck carcinoma progression reveals novel and relevant stage-specific changes associated with immortalisation and malignancy. Sci. Rep. (2019). ;9:11992.
Rehman A., Cai Y., Hünefeld C., Jedličková H., Huang Y., Teh M. T., Sharif Ahmad U., Uttagomol J., Wang Y., Kang A., Warnes G., Harwood C., Bergamaschi D., Parkinson E.K., Röcken M., Wan H. The desmosomal cadherin desmoglein-3 acts as a keratinocyte anti-stress protein via suppression of p53. Cell Death & Disease (2019) In Press
Li X., Sharif Ahmad U., Huang Y., Uttagomol J., Rehman A., Zhou K., Warnes G., McArthur S., Parkinson E.K., Wan, H. Desmoglein-3 acts as a pro-survival protein by suppressing reactive oxygen species and doming whilst augmenting the tight junctions in MDCK cells. Mech. Aging Dev. (2019) In Press
Lai S.L., Tan M.L., Hollows R.J., Robinson M,, Ibrahim M, Margielewska S., Parkinson E.K., Ramananthan A., Mehanna H., Watkins R.J., Wei W., Chung I., Murray P.G., Yap L.F., Paterson I.C. Collagen expression in head and neck cancer promotes proliferation, migration and chemo-resistance via DDR1. Cancers (2019) In Press.
REVIEWS
Parkinson, E.K. Defective responses of transformed keratinocytes to terminal differentiation stimuli. Their role in epidermal tumour promotion by phorbol esters and by deep skin wounding. Br. J. Cancer (1985), 52: 479-493.
Parkinson, E.K. and Balmain, A. Chalones revisited - a possible role for transforming growth factor in tumour promotion. Carcinogenesis (1990) 11: 195-198.
Parkinson, E.K. Do telomerase antagonists represent a novel anticancer strategy? Br. J. Cancer (1996) 73: 1-4.
Parkinson, E.K., Newbold, R.F. and Keith, W.N. The genetic basis of human keratinocyte immortalization in squamous cell carcinoma development: The role of telomerase reactivation. Eur. J. Cancer (Special Issue on Telomerase) (1997), 33: 727-734.

BOOK CHAPTERS
Edwards, J.G. and Parkinson, E.K. Locomotory Interactions between epithelial cells and fibroblasts in vitro. In: Cell behaviour. Ed. Bellairs R., Curtis, A., Dunn, G. Cambridge University Press (1982) 349-358.
Parkinson, E.K. The transformation of human epidermal keratinocytes by carcinogens and viruses in vitro. In "Carcinogenesis a Comprehensive Survey, Vol. 11 "Skin Tumors, Experimental and Clinical Aspects" (Conti, C.J., Slaga, T.J. and Klein-Szanto, A.J.P. eds), pp 349-363. Raven Press New York (1989).
Parkinson, E.K. and Yeudall, W.A. Epidermis In "Human Cancer in Primary Culture, A Handbook" (Masters, J.R.W. ed) Kluwer Academic Publishers (1991), pp 187-197.
Parkinson, E.K.and Yeudall, W. A. The Epidermis. In "The Culture of Specialised Cells" Vol. 1 Epithelial Cells (Freshney, R.I. ed), Alan R. Liss Inc. New York (1992) pp59-80.
Parkinson, E.K. Epidermal keratinocyte stem cells: Their maintenance and regulation. Seminars in Cell Biology (1992), 3, 435-444..Parkinson, E.K. Human keratinocyte immortalization: Genetic basis and its role in squamous cell carcinoma development. Culture of Immortalized Cells, Freshney, R.I., and Freshney, M.G. ed. (1996). pp 1-24 Wiley-Liss, New York.
Edington,K.G., Berry, I.J., O'Prey, M., Burns, J.E., Clark, L.J., Mitchell, R., Robertson, G., Soutar, D., Coggins, L.W. and Parkinson, E.K.In vitro analysis of multistage squamous carcinoma : Defective terminal maturation is an early and ubiquitous event. In "Culture of Specialised Cells" Vol. 4 Culture of Tumour Cells (Freshney, R.I. ed), Alan R. Liss Inc. New York (2003) pp261-288
Gordon, K.E. and Parkinson E.K. Analysis of telomerase activity and telomere function in cancer. Methods Mol. Biol. (2004) 281: 333-348.