Dr Lee Parry
Senior Research Fellow
- parryl3@cardiff.ac.uk
- +44 (0)29 2068 8017
- Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ
- Media commentator
Overview
Research overview
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 genes and 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.
Biography
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.
Publications
2020
- May, S.et al. 2020. Impact of black raspberries on the normal and malignant Apc deficient murine gut microbiome. Journal of Berry Research 10(1), pp. 61-76. (10.3233/JBR-180372)
- May, S., Parry, C. and Parry, L. 2020. Berry chemoprevention: do berries decrease the window of opportunity for tumourigenesis. Food Frontiers
2019
- Kannen, V., Parry, L. and Martin, F. L. 2019. Phages enter the fight against colorectal cancer. Trends in Cancer 5(10), pp. 577-579. (10.1016/j.trecan.2019.08.002)
- Parry, L. and Phesse, T. J. 2019. FXR regulates intestinal stem cells response to bile acids in a high fat diet. Biotarget 3(12) (10.21037/biotarget.2019.07.01)
- Young, M. A.et al. 2019. Epigenetic regulation of Dlg1, via Kaiso, alters mitotic spindle polarity and promotes intestinal tumourigenesis. Molecular Cancer Research 17(3), pp. 686-696. (10.1158/1541-7786.MCR-18-0280)
2018
- Greenow, K. R.et al. 2018. Lect2 deficiency is characterised by altered cytokine levels and promotion of intestinal tumourigenesis. Oncotarget 9(92), pp. 36430-36443. (10.18632/oncotarget.26335)
- May, S.et al. 2018. Mbd2 enables tumourigenesis within the intestine while preventing tumour-promoting inflammation. Journal of Pathology 245(3), pp. 270-282. (10.1002/path.5074)
2017
- Colbeck, E. J.et al. 2017. Treg depletion licenses T cell-driven HEV neogenesis and promotes tumor destruction. Cancer Immunology Research 5(11), pp. 1005-1015. (10.1158/2326-6066.CIR-17-0131)
- Planells-Palop, V.et al. 2017. Human germ/stem cell-specific gene TEX19 influences cancer cell proliferation and cancer prognosis. Molecular Cancer 16, article number: 84. (10.1186/s12943-017-0653-4)
- May, S., Evans, S. and Parry, L. 2017. Organoids, organs-on-chips and other systems, and microbiota. Emerging Topics in Life Sciences 1(4), pp. 385-400. (10.1042/ETLS20170047)
2016
- Hollins, A. J. and Parry, L. 2016. Long-term culture of intestinal cell progenitors: an overview of their development, application, and associated technologies. Current Pathobiology Reports 4(4), pp. 209-219. (10.1007/s40139-016-0119-1)
- Schmidt, N.et al. 2016. Epigenetic silencing of serine protease HTRA1 drives polyploidy. BMC Cancer 16, article number: 399. (10.1186/s12885-016-2425-8)
- Zhao, C.et al. 2016. Dual regulatory switch through interactions of Tcf7l2/Tcf4 with stage-specific partners propels oligodendroglial maturation. Nature Communications 7, article number: 10883. (10.1038/ncomms10883)
2015
- Parry, L.et al. 2015. Protocols for analyzing the role of Paneth cells in regenerating the murine intestine using conditional cre-lox mouse models. Journal of Visualized Experiments(105), article number: e53429. (10.3791/53429)
- Huels, D. J.et al. 2015. E-cadherin can limit the transforming properties of activating β‐catenin mutations. EMBO Journal 34(18), pp. 2321-2333. (10.15252/embj.201591739)
2014
- Koh, D. -.et al. 2014. KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes. Proceedings of the National Academy of Sciences of the United States of America 111(42), pp. 15078-15083. (10.1073/pnas.1318780111)
2013
- Parry, L.et al. 2013. Evidence for a crucial role of Paneth Cells in mediating the intestinal response to injury. Stem Cells 31(4), pp. 776-785. (10.1002/stem.1326)
- Jarde, T.et al. 2013. In vivo and in vitro models for the therapeutic targeting of Wnt signaling using a Tet-OΔN89β-catenin system. Oncogene 32(7), pp. 883-893. (10.1038/onc.2012.103)
- Meniel, V.et al. 2013. Cited1 deficiency suppresses intestinal tumorigenesis. PLoS Genetics 9(8), article number: e1003638. (10.1371/journal.pgen.1003638)
2012
- Smartt, H. J. M.et al. 2012. β-catenin represses expression of the tumour suppressor 15-prostaglandin dehydrogenase in the normal intestinal epithelium and colorectal tumour cells. Gut 61(9), pp. 1306-1314. (10.1136/gutjnl-2011-300817)
2011
- Parry, L. and Clarke, A. R. 2011. The roles of the methyl-CpG binding proteins in cancer. Genes & Cancer 2(6), pp. 618-630. (10.1177/1947601911418499)
2010
- Cole, A.et al. 2010. p21 loss blocks senescence following Apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium. EMBO Molecular Medicine 2(11), pp. 472-486. (10.1002/emmm.201000101)
2008
- Phesse, T.et al. 2008. Deficiency of Mbd2 attenuates Wnt induced tumourigenesis via deregulation of a novel Wnt inhibitor, Lect.2. Molecular and Cellular Biology 28(19), pp. 6094-6103. (10.1128/MCB.00539-08)
2005
- Wilson, C. H.et al. 2005. A mouse model of tuberous sclerosis 1 showing background specific early post-natal mortality and metastatic renal cell carcinoma. Human Molecular Genetics 14(13), pp. 1839-1850. (10.1093/hmg/ddi190)
2004
- Kirby, D. M.et al. 2004. NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency. The Journal of Clinical Investigation 114(6), pp. 837-845. (10.1172/JCI200420683)
2003
- Dixon, P. F.et al. 2003. Four years of monitoring for viral haemorrhagic septicaemia virus in marine waters around the United Kingdom. Disease of Aquatic Organisms 54(3), pp. 175-186. (10.3354/dao054175)
2001
- Hodges, A. K.et al. 2001. Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin. Human Molecular Genetics 10(25), pp. 2899-9205. (10.1093/hmg/10.25.2899)
- Parry, L.et al. 2001. Analysis of the TSC1 and TSC2 genes in sporadic renal cell carcinomas. British Journal of Cancer 85, pp. 1226-1230. (10.1054/bjoc.2001.2072)
2000
- Parry, L.et al. 2000. Molecular analysis of the TSC1 and TSC2 tumour suppressor genes in sporadic glial and glioneuronal tumours. Human Genetics 107(4), pp. 350-356. (10.1007/s004390000390)
1997
- Dixon, P.et al. 1997. Isolation of viral haemorrhagic septicaemia virus from Atlantic herring Clupea harengus from the Atlantic herring Clupea harengus from the English channel. Diseases of Aquatic Organisms 30(2), pp. 81-89.
- Parry, L. and Dixon, P. F. 1997. Stability of nine viral haemorrhagic septicaemia virus (VHSV) isolates in seawater. Bulletin of the European Association of Fish Pathologists 17(1), pp. 31-36.
Primary research
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 genes and 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.
References
- C. R. UK, Cancer worldwide - Common Cancers, http://www.cancerresearchuk.org/cancer-info/cancerstats/
- 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
