Professor Mark Arends
Professor of Pathology and Head of the Division.
My research interests include identification and validation of new genes involved in formation and progression of cancers, particularly colorectal cancer, gynaecological cancers, melanomas, as well as other neoplasms. This involves analysis of human cancer samples, cultured cells and in vivo model systems using both comparative pathology, molecular pathology and digital pathology approaches.
Carcinogenesis involves cellular transit from normal via precursor lesions to malignant neoplasms. These transitions are usually associated with characteristic genetic and epigenetic changes. In the bowel, these include alterations to APC (>80%), the DNA mismatch repair genes MLH1 & MSH2 (~15%), KRAS (~40%), and TP53 (~60%) amongst others, and these genes also influence the regulation of proliferation, differentiation and apoptosis. In the endometrium, these include alterations to PTEN (80-90%), the DNA mismatch repair genes MLH1 & MSH2 (~30%), and KRAS (~20%), amongst others.
High throughput array and DNA sequencing analyses have identified genes that consistently show loss or gain of copy number in colorectal tumours including BRUNOL4, PARK2 and IRS2 as new genes in colorectal cancer development and progression. Sleeping Beauty transposition studies have been used to identify new tumour-related genes, including those that cooperate with mutated APC in intestinal tumour formation, with mutant Nucleophosmin in leukaemogenesis and with mutated BRAF in melanoma development. DNA methylation studies of epigenetic silencing of cancer-related genes demonstrated involvement of MLH1, MGMT, PTEN, DNMT3B and others in the WNT/APC/B-CATENIN signalling pathway in colorectal neoplasia. In vivo models of intestinal tumourigenesis were used to determine contributions to tumour formation by mutant MSH2, KRAS, RASSF1A, GNAS, PARK2, NRBP1, PKHD1 and others. Use of knockout models validated SLX4/FANCP as a new Fanconi Anaemia gene and demonstrated that the Fanconi DNA repair pathway for interstrand DNA crosslinks was shown to be critically important in repairing both acetaldehyde-induced and formaldehyde-induced DNA damage thus protecting against tumour formation. Mutant ALDH gene models confirmed the involvement of ethanol and acetaldehyde as both mutagens and promoters in intestinal and liver tumour formation. Currently, conditional MSH2 knockout models allow investigation of ethanol and acetaldehyde as mutagens and promoters in colonic tumourigenesis.
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- Dr David Adams, Sanger Institute Cambridge
- Dr Ketan J Patel, MRC Laboratory of Molecular Biology Cambridge
- Dr Louise van der Weyden, Sanger Institute Cambridge
- Prof Malcolm Dunlop, University of Edinburgh
- Dr Susan Farrington, University of Edinburgh
- Dr Farhat Din, University of Edinburgh
- Dr Lesley Stark, University of Edinburgh
- Prof Ted Hupp, University of Edinburgh
- Prof Philippa Saunders, University of Edinburgh
- Dr George Poulogiannis, Harvard University and the Institute of Cancer Research London
- Prof Ian Tomlinson, University of Birmingham
- Prof Gordon Dougan, Sanger Institute Cambridge
Dr Ian Frayling, University of Cardiff
- Centre for Comparative Pathology, University of Edinburgh
- MRC Molecular Pathology Node, Edinburgh-St Andrews
Din S, Wong K, Müller M, Oniscu A, Hewinson J, Black C, Miller M, Jiménez-Sánchez A, Rabbie R, Rashid M, Satsangi J, Adams DJ, Arends MJ. Mutational analysis identifies therapeutic biomarkers in inflammatory bowel disease-associated colorectal cancers. Clin Cancer Res. 2018 15;24(20):5133-5142. doi: 10.1158/1078-0432. PMID: 29950348
Piper M. Treuting, Mark J. Arends, Suzanne M Dintzis. Lower Gastrointestinal Tract. In “Comparative Anatomy and Histology: a Mouse, Rat and Human Atlas”. Second edition. Chapter 12; pp213-228. Editors: Piper M. Treuting , Suzanne M. Dintzis & Kathleen S. Montine. 2018. Publisher: Academic Press. ISBN-10: 0128029005. ISBN-13: 978-0-12-802900-8
Gupta A, Anjomani-Virmouni S, Koundouros N, Dimitriadi M, Choo-Wing R, Valle A, Zheng Y, Chiu YH, Agnihotri S, Zadeh G, Asara JM, Anastasiou D, Arends MJ, Cantley LC, Poulogiannis G. PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation. Molecular Cell. 2017 Mar 16;65(6):999-1013.
Weyden LV, Arends MJ, Campbell AD, Bald T,, Wardle-Jones H, Griggs N, Velasco-Herrera MD, Tüting T, Sansom OJ, Karp NA, Clare S, Gleeson D, Ryder E, Galli A, Tuck E, Cambridge EL, Voet T,, Macaulay IC, Wong K; Sanger Mouse Genetics Project, Spiegel S7, Speak AO, Adams DJ.Genome-wide in vivo screen identifies novel host regulators of metastatic colonization Nature. 2017 Jan 12;541(7636):233-236 doi:10.1038/nature20792
Scudamore CL, Soilleux EJ, Karp NA, Smith K, Poulsom R, Herrington CS, Day MJ, Brayton CF, Bolon B, Whitelaw B, White ES, Everitt JI, Arends MJ. Recommendations for Minimum Information for Publication of Experimental Pathology Data: MINPEPA Guidelines. J Pathol. 2016 Jan;238(2):359-67. PMID: 26387837.
Pontel LB, Rosado IV, Burgos-Barragan, Garaycoechea JI, Yu R, Arends MJ, Chandrasekaran G, Broecker V, Wei W, Liu L, Swenberg JA, Crossan GP, Patel KJ. Endogenous formaldehyde is a hematopoietic stem cell genotoxin and metabolic carcinogen. Molecular Cell 2015; Oct 1; 60(1):177-88. PMID: 26412304
Garaycoechea JI, Crossan GP, Langevin F, Arends MJ, Patel KJ. Genotoxic consequences of endogenous aldehydes on mouse hematopoietic stem cell function. Nature 2012, 489: 571-575. PMID: 22922648
Crossan G, van der Weyden L, Rosado IV, Langevin F, Gaillard PH, McIntyre RE, Sanger Mouse Genetics Project, Gallagher F, Kettunen MI, Lewis DY, Brindle K, Arends MJ, Adams DJ, Patel KJ. Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi Anaemia. Nature Genetics 2011; 43: 147-152. PMID: 21240276
March HN, Rust AG, Wright NA, ten Hoeve J, de Ridder J, Eldridge M, van der Weyden L, Berns A, Gadiot J, Uren A, Kemp R, Arends MJ, Wessels L, Winton DJ, Adams DJ. Insertional mutagenesis reveals multiple networks of co-operating genes driving intestinal tumorigenesis. Nature Genetics 2011; 43 (12):1202-1209. PMID: 22057237
Langevin F, Crossan GP, Rosado IV, Arends MJ, Patel KJ. Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice Nature 2011; 475: 53-58. PMID: 21734703