Doctor Lee Parry
Originally from the South Wales valleys, my undergraduate training was completed in Cardiff University, followed by a PhD at the Institute of Medical Genetics at (what was then) the University of Wales College of Medicine. My Cancer Research Wales funded PhD was completed in the laboratory of Professors Julian Sampson and Jeremy Cheadle on the “Molecular and Functional Analysis of the Human Tumour Suppressor Genes TSC1 and TSC2”. Upon completing my PhD in 2002 I took up a Postdoctoral Fellow position at the Murdoch Children’s Research Institute (MCRI) in the Royal Children’s Hospital in Melbourne, Australia. My work there was a change of focus from the cancer genetics of my PhD as I worked in the research groups of A/Prof Henrik Dahl and David Thorburn on Complex I deficiency in mitochondria. Upon completing this post I returned to Cardiff University and to cancer genetics, working on a Cancer Research UK funded project in the laboratory of Prof Alan Clarke. In July 2013 I took up a fellowship at the European Cancer Stem Cell Research Institute where my research now focuses on understanding and therapeutically exploiting the mechanisms that links the environment (diet & gut bacteria) to inflammation and colorectal cancer.
Colorectal cancer (CRC) leads to ≈600,000 deaths globally each year and is one of the major causes of death in the western world1. In the UK it is the fourth most common cancer with ~40,000 new cases diagnosed each year (Cancer Research UK). The major CRC risk factors are diet, family history and other medical conditions. For example patients with inflammatory bowel diseases (IBDs), such as colitis or Crohn’s disease, have a 3-5 fold greater risk of developing CRC. It is therefore a concern that the ~1 in 200 prevalence rate of IBD in the western world is rising, which is at least in part due to diet.
One of the many factors that contribute to the initiation and progression of CRC is inflammation. Inflammation can support tumour development, both directly and indirectly, and tumours can promote a chronic inflammatory environment that results in immunosuppression, which benefits the tumour2. It is well documented that CRCs evolve through loops of deregulated inflammatory stimuli which are sustained by DNA damage signalling pathways and epigenetic re-modelling (DNA methylation). Intensive work in recent years has led to the identification of genesand mechanisms that link diet to changes in the gut microbiota that alter DNA methylation patterns. These alterations drive inflammatory/immune responses which interact with intestinal stem cell and can prevent or promote intestinal disease and cancer. However, to date no studies address all those elements simultaneously. The synergic analysis of such parameters could provide new biological insights and effective biomarkers that could have applications in prevention, molecular diagnosis, prognosis and treatment of intestinal disease and CRC. Thus, to complement the current reductionist approaches, which examine each of the interacting factors in isolation, there is a requirement for a more holistic approach to unravel how these factors interact. My research focuses on understanding the common mechanisms which link the environment to intestinal disease.
In recent years the importance of diet and dysbiosis of gut microbiota in driving these inflammatory loops has been recognised. The interaction between dietary intake and the microbiota has been well studied, which has led to the prediction of a driver-passenger model, where CRC can be initiated by “driver” bacteria which are eventually replaced by “passenger“ bacteria3. Intensive work in recent years using mouse models has led to the identification of genesand mechanisms that link changes in the microbiota to DNA methylation, inflammation and cancer. It is DNA methylation which links these factors together as it is a process which links the environment to phenotype altering DNA modifications. Hyper-methylated DNA in the promoter of a gene is recognised by members of the methyl binding protein (MBP) family which recruit transcriptional silencing machinery. Thus these proteins can act as master controllers, by silencing the genes that are correctly methylated or alternatively silencing genes aberrantly methylated by disease processes 4. My primary research focuses on these MBPs as they regulate genes which play a role in determining immune/inflammatory responses (e.g. IL-4, Ifng & FoxP3) and we have demonstrated that in Apcmin/+ mice the deficiency of MBPs Mbd2 or Kaiso can suppress intestinal tumourigenesis5. We are investigating the genes and pathways that these MBPs regulate in the intestinal stem cell and immune cells in altered microbiotic, inflammatory and disease environments. Understanding these mechanisms may allow us to manipulate MBPs to shift responses in disease towards relieving immunosuppression and driving antitumor immunity that, when combined with other therapies, may ultimately result in tumour cell clearance 6-8.
- C. R. UK, Cancer worldwide - Common Cancers, http://info.cancerresearchuk.org/cancerstats/geographic/world/commoncancers/
- L. M. Coussens, L. Zitvogel and A. K. Palucka, Science, 2013, 339, 286-291.
- H. Tjalsma, A. Boleij, J. R. Marchesi and B. E. Dutilh, Nat Rev Microbiol, 2012, 10, 575-582.
- L. Parry and A. R. Clarke, Genes Cancer, 2011, 2, 618-630.
- O. J. Sansom, J. Berger, S. M. Bishop, B. Hendrich, A. Bird and A. R. Clarke, Nat Genet, 2003, 34, 145-147.
- M. Har-Noy, in Oncology News, ed. R. Or, Online, 2009, pp. 110-112.
- M. Yamamoto, T. Kamigaki, K. Yamashita, Y. Hori, H. Hasegawa, D. Kuroda, H. Moriyama, M. Nagata, Y. Ku and Y. Kuroda, Oncol Rep, 2009, 22, 337-343.
- M. Tosolini, A. Kirilovsky, B. Mlecnik, T. Fredriksen, S. Mauger, G. Bindea, A. Berger, P. Bruneval, W. H. Fridman, F. Pagès and J. Galon, Cancer Res, 2011, 71, 1263-1271.