Karen Blyth - Transgenic Models

Introduction

blyth k

The Transgenic Models Lab develops and utilises sophisticated genetic models that recapitulate human cancer. Using models of intestinal cancer, pancreatic cancer, breast cancer and melanoma we can better understand how cancer cells behave and metastasise, and develop biologically relevant systems for testing novel therapeutic agents.

The lab is particularly interested in a family of genes called the RUNX genes. These genes are essential regulators in mammalian development, most notably for bone and blood cell lineages. Like many genes important for normal development, the RUNX genes are linked to human cancer, but interestingly have been found to both promote and suppress tumour formation, a paradox we are exploring. We have shown that high expression of RUNX1 and RUNX2 in breast cancer correlates with specific subtypes of the disease and with poorer patient prognosis. We are now investigating the functionality of these genes in epithelial cancers and have shown that RUNX2 has a role in mammary stem/progenitor cells.


Details of SEARCHBreast, a resource to facilitate sharing of archived material derived from in vivo breast cancer models, can be found here:

Lab Report

Key Publications

Blyth K, Carter P, Morrissey B, Chelala C, Jones L, Holen I and Speirs V. SEARCHBreast: a new resource to locate and share surplus archival material from breast cancer animal models to help address the 3Rs. Breast Cancer Res Treat 56(3):447-52, 2016

Ferrari N, Riggio AI, Mason S, McDonald L, King A, Higgins T, Rosewell I, Neil JC, Smalley MJ, Sansom OJ, Morris J, Cameron ER, Blyth K. Runx2 contributes to the regenerative potential of the mammary epithelium. Scientific Reports 5:15658, 2015

Ferrari N, Mohammed ZMA, Nixon C, Mason SM, Mallon E, McMillan DC, Morris JS, Cameron ER, Blyth K. Expression of RUNX1 correlates with poor patient prognosis in triple negative breast cancer. PLOS One 9(6):e100759, 2014

McDonald L, Ferrari N, Terry A, Bell M, Mohammed ZM, Orange C, Jenkins A, Muller WJ, Gusterson BA, Neil JC, Edwards J, Morris JS, Cameron ER, Blyth K. RUNX2 correlates with subtype-specific breast cancer in a human tissue microarray and ectopic expression of Runx2 perturbs differentiation in the mouse mammary gland. Dis Model Mech 7(5):525-34, 2014

Blyth K, Vaillant F, Hanlon L, Mackay N, Bell M, Jenkins A, Neil JC, Cameron ER. Runx2 and MYC collaborate in lymphoma development by suppressing apoptotic and growth arrest pathways in vivo. Cancer Res. 66(4):2195-201, 2006

Blyth K, Cameron ER, Neil JC. The RUNX genes: gain or loss of function in cancer. Nat Rev Cancer 5(5):376-87, 2005

Biography

Education and qualifications

1997: PhD, University of Glasgow, Supervisors Ewan Cameron & Moyra Campbell
1991: BSc, Biochemistry (Honours), University of Glasgow

Appointments

2009-present: Head of Transgenic Models, Cancer Research UK Beatson Institute, Glasgow
2009-present: Honorary Senior Lecturer, University of Glasgow
1997-2008: Postdoctoral Fellow, Molecular Oncology Lab, University of Glasgow
1991-1996: Research Assistant, University of Glasgow

Recent Publications

2018

Campbell KJ, Dhayade S, Ferrari N, Sims AH, Johnson E, Mason SM, Dickson A, Ryan KM, Kalna G, Edwards J, Tait SWG, Blyth K. MCL-1 is a prognostic indicator and drug target in breast cancer. Cell Death Dis 2018; 9. doi: 10.1038/s41419-017-0035-2. [Epub ahead of print]

McCarroll CS, He W, Foote K, Bradley A, McGlynn K, Vidler F, Nixon C, Nather K, Fattah C, Riddell AH, Bowman P, Elliott EB, Bell M, Hawksby C, MacKenzie SM, Morrison LJ, Terry A, Blyth K, Smith GL, McBride MW et al. Runx1 Deficiency Protects Against Adverse Cardiac Remodeling Following Myocardial Infarction. Circulation 2018; 137: 57-70.

2017

Bulusu V, Tumanov S, Michalopoulou E, van den Broek NJ, MacKay G, Nixon C, Dhayade S, Schug ZT, Vande Voorde J, Blyth K, Gottlieb E, Vazquez A, Kamphorst JJ. Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation. Cell Rep 2017; 18: 647-58

Dornier E, Rabas N, Mitchell L, Novo D, Dhayade S, Marco S, Mackay G, Sumpton D, Pallares M, Nixon C, Blyth K, Macpherson I, Rainero E, Norman JC. Glutaminolysis drives membrane trafficking to promote cancer invasion. Nat Commun 2017; 8: 2255.

Giampazolias E, Zunino B, Dhayade S, Bock F, Cloix C, Cao K, Roca A, Lopez J, Ichim G, Proics E, Rubio-Patino C, Fort L, Yatim N, Woodham E, Orozco S, Taraborrelli L, Peltzer N, Lecis D, Machesky L, Walczak H et al. Mitochondrial permeabilization engages NF-kappaB-dependent anti-tumour activity under caspase deficiency. Nat Cell Biol 2017; 19: 1116-29

Hernandez-Fernaud JR, Ruengeler E, Casazza A, Neilson LJ, Pulleine E, Santi A, Ismail S, Lilla S, Dhayade S, MacPherson IR, McNeish I, Ennis D, Ali H, Kugeratski FG, Al Khamici H, van den Biggelaar M, van den Berghe PV, Cloix C, McDonald L, Millan D et al. Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity. 2017 Nat Commun 8: 14206

Hock AK, Cheung EC, Humpton TJ, Monteverde T, Paulus-Hock V, Lee P, McGhee E, Scopelliti A, Murphy DJ, Strathdee D, Blyth K, Vousden KH. Development of an inducible mouse model of iRFP713 to track recombinase activity and tumour development in vivo. Sci Rep 2017; 7: 1837

Loveridge CJ, Mui EJ, Patel R, Tan EH, Ahmad I, Welsh M, Galbraith J, Hedley A, Nixon C, Blyth K, Sansom O, Leung HY. Increased T-cell Infiltration Elicited by Erk5 Deletion in a Pten-Deficient Mouse Model of Prostate Carcinogenesis. Cancer Res 2017; 77: 3158-68

Loveridge CJ, van 't Hof RJ, Charlesworth G, King A, Tan EH, Rose L, Daroszewska A, Prior A, Ahmad I, Welsh M, Mui EJ, Ford C, Salji M, Sansom O, Blyth K, Leung HY. Analysis of Nkx3.1:Cre-driven Erk5 deletion reveals a profound spinal deformity which is linked to increased osteoclast activity. Sci Rep 2017; 7: 13241

Maddocks ODK, Athineos D, Cheung EC, Lee P, Zhang T, van den Broek NJF, Mackay GM, Labuschagne CF, Gay D, Kruiswijk F, Blagih J, Vincent DF, Campbell KJ, Ceteci F, Sansom OJ, Blyth K, Vousden KH. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature 2017; 544: 372-6

Reid SE, Kay EJ, Neilson LJ, Henze AT, Serneels J, McGhee EJ, Dhayade S, Nixon C, Mackey JB, Santi A, Swaminathan K, Athineos D, Papalazarou V, Patella F, Roman-Fernandez A, ElMaghloob Y, Hernandez-Fernaud JR, Adams RH, Ismail S, Bryant DM et al. Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium. EMBO J 2017; 36: 2373-89

Rumney RMH, Coffelt SB, Neale TA, Dhayade S, Tozer GM, Miller G. PyMT-Maclow: A novel, inducible, murine model for determining the role of CD68 positive cells in breast tumor development. PLoS One 2017; 12: e0188591

van Tuyn J, Jaber-Hijazi F, MacKenzie D, Cole JJ, Mann E, Pawlikowski JS, Singh Rai T, Nelson DM, McBryan T, Ivanov A, Blyth K, Wu H, Milling S, Adams PD. Oncogene-Expressing Senescent Melanocytes Upregulate Mhc Class Ii, A Candidate Melanoma Suppressor Function. J Invest Dermatol 2017; 137: 2197-207

Walton JB, Farquharson M, Mason S, Port J, Kruspig B, Dowson S, Stevenson D, Murphy D, Matzuk M, Kim J, Coffelt S, Blyth K, McNeish IA.
CRISPR/Cas9-derived models of ovarian high grade serous carcinoma targeting Brca1, Pten and Nf1, and correlation with platinum sensitivity. Sci Rep 2017;7: 16827

Weigert M, Binks A, Dowson S, Leung EYL, Athineos D, Yu X, Mullin M, Walton JB, Orange C, Ennis D, Blyth K, Tait SWG, McNeish IA. RIPK3 promotes adenovirus type 5 activity. Cell Death and Disease 2017; 8: 3206

Holen I, Speirs V, Morrissey B, Blyth K. In vivo models in breast cancer research: progress, challenges and future directions. Dis Model Mech 2017; 10: 359-71

Morrissey B, Blyth K, Carter P, Chelala C, Jones L, Holen I, Speirs V. The Sharing Experimental Animal Resources, Coordinating Holdings (SEARCH) Framework: Encouraging Reduction, Replacement, and Refinement in Animal Research. PLoS Biol 2017 15: e2000719

Riggio AI, Blyth K. The Enigmatic Role of RUNX1 in Female-Related Cancers: Current Knowledge & Future Perspectives. FEBS J 2017; 284: 2345-62

Rooney N, Riggio AI, Mendoza-Villanueva D, Shore P, Cameron ER, Blyth K. Runx Genes in Breast Cancer and the Mammary Lineage. Adv Exp Med Biol 2017; 962: 353-68

2016

Meiser J, Tumanov S, Maddocks O, Labuschagne CF, Athineos D, Van Den Broek N, Mackay GM, Gottlieb E, Blyth K, Vousden K, Kamphorst JJ, Vazquez A. Serine one-carbon catabolism with formate overflow. Science Advances 2: e1601273, 2016

Birch J, Clarke CJ, Campbell AD, Campbell K, Mitchell L, Liko D, Kalna G, Strathdee D, Sansom OJ, Neilson M, Blyth K, Norman JC. The initiator methionine tRNA drives cell migration and invasion leading to increased metastatic potential in melanoma. Biol Open. 2016 Aug 19. pii: bio.019075. doi: 10.1242/bio.019075. [Epub ahead of print]

Walton J, Blagih J, Ennis D, Leung E, Dowson S, Farquharson M, Tookman LA, Orange C, Athineos D, Mason S, Stevenson D, Blyth K, Strathdee D, Balkwill FR, Vousden KH, Lockley M, McNeish IA.CRISPR/Cas9-mediated Trp53 and Brca2 knockout to generate improved murine models of ovarian high grade serous carcinoma. Cancer Res. 2016 Aug 16. pii: canres.1272.2016. [Epub ahead of print]

2015

Cardaci S, Zheng L, MacKay G, van den Broek NJ, MacKenzie ED, Nixon C, Stevenson D, Tumanov S, Bulusu V, Kamphorst JJ, Vazquez A, Fleming S, Schiavi F, Kalna G, Blyth K, Strathdee D, Gottlieb E. Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis. Nat Cell Biol 17: 1317-26, 2015

Dikovskaya D, Cole JJ, Mason SM, Nixon C, Karim SA, McGarry L, Clark W, Hewitt RN, Sammons MA, Zhu J, Athineos D, Leach JD, Marchesi F, van Tuyn J, Tait SW, Brock C, Morton JP, Wu H, Berger SL, Blyth K, Adams PD. Mitotic Stress Is an Integral Part of the Oncogene-Induced Senescence Program that Promotes Multinucleation and Cell Cycle Arrest. Cell Rep 12: 1483-96, 2015

Ferrari N, Riggio AI, Mason S, McDonald L, King A, Higgins T, Rosewell I, Neil JC, Smalley MJ, Sansom OJ, Morris J, Cameron ER, Blyth K. Runx2 contributes to the regenerative potential of the mammary epithelium. Sci Rep 5: 15658, 2015

Hunter JE, Butterwurth JA, Zhao B, Sellier H, Campbell KJ, Thomas HD, Bacon CM, Cockell SJ, Gewurz BE, Perkins ND. The NF-kB subunit c-Rel regulated Bach2 tumour suppressor expression in B-cell lymphoma. Oncogene 2015. doi: 10.1038/onc.2015.399. Epub 2015 Nov 2

Ichim G, Lopez J, Ahmed SU, Muthalagu N, Giampazolias E, Delgado ME, Haller M, Riley JS, Mason SM, Athineos D, Parsons MJ, van de Kooij B, Bouchier-Hayes L, Chalmers AJ, Rooswinkel RW, Oberst A, Blyth K, Rehm M, Murphy DJ, Tait SW. Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. Mol Cell 57: 860-72, 2015

Iglesias JM, Cairney CJ, Ferrier RK, McDonald L, Soady K, Kendrick H, Pringle MA, Morgan RO, Martin F, Smalley MJ, Blyth K, Stein T. Annexin A8 identifies a subpopulation of transiently quiescent c-kit positive luminal progenitor cells of the ductal mammary epithelium. PLoS One 10: e0119718, 2015

Moniz S, Bandarra D, Biddlestone J, Campbell KJ, Komander D, Bremm A, Rocha S. Cezanne regulates E2F1-dependent HIF2a expression. J Cell Sci 2015; 128: 3082-93

Naseer A, Terry A, Gilroy K, Kilbey A, Watts C, Mackay N, Bell M, Mason S, Blyth K, Cameron E, Neil JC. Frequent infection of human cancer xenografts with murine endogenous retroviruses in vivo. Viruses 7: 2014-29, 2015

Pawlikowski JS, Brock C, Chen SC, Al-Olabi L, Nixon C, McGregor F, Paine S, Chanudet E, Lambie W, Holmes WM, Mullin JM, Richmond A, Wu H, Blyth K, King A, Kinsler VA, Adams PD. Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling. J Invest Dermatol 135: 2093-101, 2015

Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS, Goodwin LM, Smethurst E, Mason S, Blyth K, McGarry L, James D, Shanks E, Kalna G, Saunders RE, Jiang M, Howell M, Lassailly F, Thin MZ, Spencer-Dene B, Stamp G, van den Broek NJ, Mackay G, Bulusu V, Kamphorst JJ, Tardito S, Strachan D, Harris AL, Aboagye EO, Critchlow SE, Wakelam MJ, Schulze A, Gottlieb E. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27: 57-71, 2015

Zheng L, Cardaci S, Jerby L, MacKenzie ED, Sciacovelli M, Johnson TI, Gaude E, King A, Leach JD, Edrada-Ebel R, Hedley A, Morrice NA, Kalna G, Blyth K, Ruppin E, Frezza C, Gottlieb E. Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nat Commun 6: 6001, 2015

2014

Ferrari N, Mohammed ZM, Nixon C, Mason SM, Mallon E, McMillan DC, Morris JS, Cameron ER, Edwards J, Blyth K. Expression of RUNX1 Correlates with Poor Patient Prognosis in Triple Negative Breast Cancer. PLoS One 9: e100759, 2014

Li A, Morton JP, Ma Y, Karim SA, Zhou Y, Faller WJ, Woodham EF, Morris HT, Stevenson RP, Juin A, Jamieson NB, MacKay CJ, Carter CR, Leung HY, Yamashiro S, Blyth K, Sansom OJ, Machesky LM. Fascin is regulated by slug, promotes progression of pancreatic cancer in mice, and is associated with patient outcomes. Gastroenterology 146: 1386-96 e1-17, 2014

McDonald L, Ferrari N, Terry A, Bell M, Mohammed ZM, Orange C, Jenkins A, Muller WJ, Gusterson BA, Neil JC, Edwards J, Morris JS, Cameron ER, Blyth K. RUNX2 correlates with subtype-specific breast cancer in a human tissue microarray, and ectopic expression of Runx2 perturbs differentiation in the mouse mammary gland. Dis Model Mech 7: 525-34, 2014

Rai TS, Cole JJ, Nelson DM, Dikovskaya D, Faller W, Vizioli MG, Hewitt RN, Anannya O, McBryan T, Manoharan I, van Tuyn J, Morrice N, Pchelintsev NA, Ivanov A, Brock C, Drotar M, Nixon C, Clark W, Sansom OJ, Anderson KI, King A, Blyth K, Adams PD. HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia. Genes Dev 28: 2712-25, 2014

Vandenberg CJ, Josefsson EC, Campbell KJ, James C, Lawlor KE, Kile BT, Cory S. Loss of Bak enhances lymphocytosis but does not ameliorate thrombocyteppaenia in BCL-2 transgenic mice. Cell Death Differ 21: 676-84, 2014

2013

Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, Athineos D, Kang TW, Lasitschka F, Andrulis M, Pascual G, Morris KJ, Khan S, Jin H, Dharmalingam G, Snijders AP, Carroll T, Capper D, Pritchard C, Inman GJ, Longerich T, Sansom OJ, Benitah SA, Zender L, Gil J. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 15: 978-90, 2013

Cheung EC, Athineos D, Lee P, Ridgway RA, Lambie W, Nixon C, Strathdee D, Blyth K, Sansom OJ, Vousden KH. TIGAR is required for efficient intestinal regeneration and tumorigenesis. Dev Cell 25: 463-77, 2013 Epub 2013/06/04.

Hock AK, Lee P, Maddocks OD, Mason SM, Blyth K, Vousden KH. iRFP is a sensitive marker for cell number and tumor growth in high-throughput systems. Cell Cycle 13, 2013

Myant KB, Cammareri P, McGhee EJ, Ridgway RA, Huels DJ, Cordero JB, Schwitalla S, Kalna G, Ogg EL, Athineos D, Timpson P, Vidal M, Murray GI, Greten FR, Anderson KI, Sansom OJ. ROS production and NF-kappaB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell Stem Cell 12: 761-73, 2013

Pawlikowski JS, McBryan T, van Tuyn J, Drotar ME, Hewitt RN, Maier AB, King A, Blyth K, Wu H, Adams PD. Wnt signaling potentiates nevogenesis. Proc Natl Acad Sci U S A 110: 16009-14, 2013

Radulescu S, Ridgway RA, Cordero J, Athineos D, Salgueiro P, Poulsom R, Neumann J, Jung A, Patel S, Woodgett J, Barker N, Pritchard DM, Oien K, Sansom OJ. Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation. Oncogene 32: 2048-57, 2013

Wiese KE, Walz S, von Eyss B, Wolf E, Athineos D, Sansom O, Eilers M. The Role of MIZ-1 in MYC-Dependent Tumorigenesis. Cold Spring Harb Perspect Med 3, 2013

Zheng L, Mackenzie ED, Karim SA, Hedley A, Blyth K, Kalna G, Watson DG, Szlosarek P, Frezza C, Gottlieb E. Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells. Cancer Metab 1: 12, 2013

2012

Li A, Ma Y, Jin M, Mason S, Mort RL, Blyth K, Larue L, Sansom OJ, Machesky LM. Activated Mutant NRas(Q61K) Drives Aberrant Melanocyte Signaling, Survival, and Invasiveness via a Rac1-Dependent Mechanism. J Invest Dermatol 2012; 132: 21610-21

Maddocks ODK, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, Vousden KH. Serine starvation induces stress and p53 dependent metabolic remodeling in cancer cells. Nature doi: 10.1038/nature11743, published online 16 Dec 2012

Ridgway RA, Serrels B, Mason S, Kinnaird A, Muir M, Patel H, Muller WJ, Sansom OJ, Brunton VG. Focal adhesion kinase is required for beta-catenin-induced mobilization of epidermal stem cells. Carcinogenesis 2012; 33: 2369-76

Radulescu S, Ridgway RA, Cordero J, Athineos D, Salgueiro P, Poulsom R, Neumann J, Jung A, Patel S, Woodgett J, Barker N, Pritchard DM, Oien K, Sansom OJ. Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation. Oncogene doi: 10.1038/onc.2012.224, published online 4 Jun 2012
Yu X, Zech T, McDonald L, Gonzalez EG, Li A, Macpherson I, Schwarz JP, Spence H, Futo K, Timpson P, Nixon C, Ma Y, Anton IM, Visegrady B, Insall RH, Oien K, Blyth K, Norman JC, Machesky LM. N-WASP coordinates the delivery and F-actin-mediated capture of MT1-MMP at invasive pseudopods. J Cell Biol 2012; 199: 527-44

Zebisch A, Wolfler A, Fried I, Wolf O, Lind K, Bodner C, Haller M, Drasche A, Pirkebner D, Matallanas D, Rath O, Blyth K, Delwel R, Taskesen E, Quehenberger F, Kolch W, Troppmair J, Sill H. Frequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia. Leukemia 2012; 26: 1842-9

Lab Members

blyth group

Post-doc

Nicholas Rooney

Scientific Officers

Dimitris Athineos
Sandeep Dhayade
Susan Mason

PhD Student

Alessandra Riggio

Research

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Read more about the Research Groups working at the Beatson Institute.

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Seminars

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Find out more about our seminars including our Distinguished Seminar Programme.

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