Professor Mark Arends
Professor of Pathology and Head of Edinburgh Pathology.
My research interests include identification and validation of new genes involved in formation and progression of neoplasms, particularly colorectal cancer including inflammatory bowel disease-associated colorectal cancer and its precursor dysplastic lesions, gynaecological cancers, melanomas, other skin tumours, leukaemias, 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/computational 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.
Modern methods of DNA sequence analysis have identified genes that consistently show mutations, or 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. Organ-specific 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 Shahida Din, NHS Lothian & University of Edinburgh
- Dr Guia Cerretelli, University of Edinburgh
- 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
Dr Ian Frayling, University of Cardiff
- Centre for Comparative Pathology, University of Edinburgh
- MRC Molecular Pathology Node, Edinburgh-St Andrews
Cerretelli G, Zhou Y, Müller MF, Adams DJ, Arends MJ, "Acetaldehyde and defective mismatch repair increase colonic tumours in a Lynch Syndrome model with Aldh1b1 inactivation." Disease Models & Mechanisms 2023 August 16 (8): 1-11. dmm.050240. doi: 10.1242/dmm.050240. PMID: 37395714.
Sodir NM, Pellegrinet L, Kortlever RM, Campos T, Kwon YW, Kim S, Garcia D, Perfetto A, Anastasiou P, Swigart LB, Arends MJ, Littlewood TD, Evan GI, "Reversible Myc hypomorphism identifies a key Myc-dependency in early cancer evolution", Nature Communications 2022 Nov 9;13(1):6782. doi:10.1038/s41467-022-34079-x, PMID: 36351945.
Mulderrig L, Garaycoechea JI, Tuong ZK, Millington CL, Dingler FA, Ferdinand JR, Gaul L, Tadross JA, Arends MJ, O'Rahilly S, Crossan GP, Clatworthy MR, Patel KJ, "Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response" Nature 2021 Dec;600(7887):158-163, doi:10.1038/s41586-021-04133-7, Epub 2021 Nov 24, PMID: 34819667.
Cerretelli G, Zhou Y, Müller MF, Adams DJ, Arends MJ, "Ethanol-induced formation of colorectal tumours and precursors in a mouse model of Lynch Syndrome" Journal of Pathology 2021 Dec;255(4):464-474. doi:10.1002/path.5796, Epub 2021 Oct 13, PMID: 34543445.
Cerretelli G, Ager A, Arends MJ, Frayling IM, "Molecular Pathology of Lynch Syndrome" Journal of Pathology 2020 Apr;250(5):518-531, doi:10.1002/path.5422, PMID: 32141610.
Crosbie EJ, Ryan NAJ, Arends MJ, Bosse T, Burn J, Cornes J, Crawford RAF, Eccles D, Frayling I, Ghaem-Maghani S, Hampel H, Kauff N, Kitchener HC, Kitson SJ, Manchanda R, McMahon R, Monahan KJ, Menon U, Moller P, Moeslein G, Rosenthal A, Sasieni P, Seif M, Singh N, Skarrott P, Snowsill T, Steele R, Tischkowitz M, Manchester International Consensus Group, Evans DG. "The Manchester International Consensus Group Recommendations for the Management of Gynecological Cancers in Lynch Syndrome", Genetics in Medicine 2019 Oct;21(10):2390-2400, doi:10.1038/s41436-019-0489-y, PMID: 30918358.
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.CCR-17-3713, PMID: 29950348
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, doi:10.1016/j.molcel.2017.02.019
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
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, doi:10.1016/j.molcel.2015.08.020, 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. doi:10.1038/nature11368, 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, doi:10.1038/ng.752, 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, doi:10.1038/ng.990, 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, doi:10.1038/nature10192, PMID: 21734703.