Transgenic Models of Cancer
Introduction
Professor Karen BlythHead of Transgenic Models of Cancer Facility |
The Transgenic Models of Cancer lab uses in vivo models to recapitulate human cancer and interrogate all aspects of disease progression within a biological context (from early disease through to metastasis and recurrence). Validating in vitro discoveries in physiologically relevant models in this way will expedite novel therapeutic approaches for patient benefit. The group has expertise in modelling different cancer types using state-of-the art genetic and refined transplantation models to interrogate how oncogenic pathways, altered metabolism and the tumour microenvironment contribute to cancer.
The Scotland Institute is renowned for its application of in vivo modelling to address key cancer questions. At the core of this is the Transgenic Models Lab, headed by Karen Blyth, which facilitates collaborative science with many of our colleagues at the Scotland Institute, University of Glasgow, as well as external research groups. Cancers spontaneously grow at their site of origin, invade surrounding tissue and colonise distant organs which occurs through a complex array of processes, and which can be distinct between different tumour types. So interrogating aspects of this multifaceted behaviour in a plastic dish has obvious limitations. It is important therefore to use physiologically relevant models in which tumours arise and mature in their natural environment. In this way, tumour cells directly and spatially co-evolve with stromal fibroblasts, immune cells and the endothelium recapitulating a more accurate tumour microenvironment, are exposed to metabolic limiting conditions, and have to negotiate biological barriers in order to metastasise. Furthermore, many anti-cancer drugs fail in the clinic because although they are effective in simplified tissue culture models, the nuances of taking these drugs into the whole animal setting cannot be ignored.
Karen Blyth also leads the In Vivo Cancer Biology research group.
Recent Publications
2023
Santi A, Kay EJ, Neilson LJ, McGarry L, Lilla S, Mullin M, Paul NR, Fercoq F, Koulouras G, Blanco GR, Athineos D, Mason S, Hughes M, Kieffer Y, Nixon C, Blyth K, Mechta-Grigoriou F, Carlin LM, Zanivan S. Cancer-associated fibroblasts produce matrix-bound vesicles that influence endothelial cell function. bioRxiv. 2023;Volume:2023.2001.2013.523951.
2022
Falcone M, Uribe AH, Papalazarou V, Newman AC, Athineos D, Stevenson K, Sauvé CG, Gao Y, Kim JK, Del Latto M, Kierstead M, Wu C, Smith JJ, Romesser PB, Chalmers AJ, Blyth K, Maddocks ODK. Sensitisation of cancer cells to radiotherapy by serine and glycine starvation. Br J Cancer. 2022;127:1773-1786.
Kay EJ, Paterson K, Riero-Domingo C, Sumpton D, Däbritz JHM, Tardito S, Boldrini C, Hernandez-Fernaud JR, Athineos D, Dhayade S, Stepanova E, Gjerga E, Neilson LJ, Lilla S, Hedley A, Koulouras G, McGregor G, Jamieson C, Johson RM, Park M, Kirschner K, Miller C, Kamphorst JJ, Loayza-Puch F, Saez-Rodriguez J, Mazzone M, Blyth K, Zagoni M, Zanivan S. Cancer-associated fibroblasts require proline synthesis by PYCR1 for the deposition of pro-tumorigenic extracellular matrix. Nature Metabolism. 2022;4(6):693-710.
2021
Humpton TJ, Nomura K, Weber J, Magnussen HM, Hock AK, Nixon C, Dhayade S, Stevenson D, Huang DT, Strathdee D, Blyth K, Vousden KH. Differential requirements for MDM2 E3 activity during embryogenesis and in adult mice. Genes & development. 2021;35(1-2):117-132.
Latif AL, Newcombe A, Li S, Gilroy K, Robertson NA, Lei X, Stewart HJS, Cole J, Terradas MT, Rishi L, McGarry L, McKeeve C, Reid C, Clark W, Campos J, Kirschner K, Davis A, Lopez J, Sakamaki JI, Morton JP, et al. BRD4-mediated repression of p53 is a target for combination therapy in AML. Nat Commun. 2021;12:241.
Nacke M, Sandilands E, Nikolatou K, Román-Fernández Á, Mason S, Patel R, Lilla S, Yelland T, Galbraith LCA, Freckmann EC, McGarry L, Morton JP, Shanks E, Leung HY, Markert E, Ismail S, Zanivan S, Blyth K, Bryant DM. An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism. Nat Commun. 2021;12:1623.
Newman AC, Falcone M, Huerta Uribe A, Zhang T, Athineos D, Pietzke M, Vazquez A, Blyth K, Maddocks ODK. Immune-regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells. Mol Cell. 2021:81;2290-2302
Tajan M, Hennequart M, Cheung EC, Zani F, Hock AK, Legrave N, Maddocks ODK, Ridgway RA, Athineos D, Suárez-Bonnet A, Ludwig RL, Novellasdemunt L, Angelis N, Li VSW, Vlachogiannis G, Valeri N, Mainolfi N, Suri V, Friedman A, Manfredi M, et al. Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy. Nat Commun. 2021;12:366.
2020
Blagih J, Zani F, Chakravarty P, Hennequart M, Pilley S, Hobor S, Hock AK, Walton JB, Morton JP, Gronroos E, Mason S, Yang M, McNeish I, Swanton C, Blyth K, Vousden KH. Cancer-Specific Loss of p53 Leads to a Modulation of Myeloid and T Cell Responses. Cell reports. 2020;30:481-496.e486.
Campbell KJ, Blyth K Somatic base editing to model oncogenic drivers in breast cancer Lab Anim. 2020; 49: 115–116
Caraffini V, Geiger O, Rosenberger A, Hatzl S, Perfler B, Berg JL, Lim C, Strobl H, Kashofer K, Schauer S, Beham-Schmid C, Hoefler G, Geissler K, Quehenberger F, Kolch W, Athineos D, Blyth K, Wolfler A, Sill H, Zebisch A. Loss of RAF kinase inhibitor protein is involved in myelomonocytic differentiation and aggravates RAS-driven myeloid leukemogenesis. Haematologica. 2020;
Cheung EC, DeNicola GM, Nixon C, Blyth K, Labuschagne CF, Tuveson DA, Vousden KH. Dynamic ROS Control by TIGAR Regulates the Initiation and Progression of Pancreatic Cancer. Cancer cell. 2020; 37: 168-182
Dhayade S, Pietzke M, Wiesheu R, Tait-Mulder J, Athineos D, Sumpton D, Coffelt S, Blyth K, Vazquez A. Impact of Formate Supplementation on Body Weight and Plasma Amino Acids. Nutrients. 2020; 12(8):2181.
Lie ALM, Mevel R, Patel R, Blyth K, Baena E, Kouskoff V, Lacaud G. RUNX1 Dosage in Development and Cancer. Mol Cells. 2020; 43: 126-128
Loveridge CJ, Slater S, Campbell KJ, Nam NA, Knight J, Ahmad I, Hedley A, Lilla S, Repiscak P, Patel R, Salji M, Fleming J, Mitchell L, Nixon C, Strathdee D, Neilson M, Ntala C, Bryson S, Zanivan S, Edwards J, Robson CN, Goodyear CS, Blyth K, Leung HY. BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration. Oncogene. 2020; 39: 1797–1806
MacKenzie DJ, Robertson NA, Rather I, Reid C, Sendzikaite G, Cruickshanks H, McBryan T, Hodges A, Pritchard C, Blyth K, Adams PD. DNMT3B Oncogenic Activity in Human Intestinal Cancer Is Not Linked to CIMP or BRAFV600E Mutation. iScience. 2020;23:100838-100838.
Millar R, Kilbey A, Remak SJ, Severson TM, Dhayade S, Sandilands E, Foster K, Bryant DM, Blyth K, Coffelt SB. The MSP-RON axis stimulates cancer cell growth in models of triple negative breast cancer. Molecular oncology. 2020;14: 1868-1880
Oizel K, Tait-Mulder J, Fernandez-de-Cossio-Diaz J, Pietzke M, Brunton H, Lilla S, Dhayade S, Athineos D, Blanco GR, Sumpton D, Mackay GM, Blyth K, Zanivan SR, Meiser J, Vazquez A. Formate induces a metabolic switch in nucleotide and energy metabolism. Cell death & disease. 2020;11:310.
Ran R, Harrison H, Syamimi Ariffin N, Ayub R, Pegg HJ, Deng W, Mastro A, Ottewell PD, Mason SM, Blyth K, Holen I, Shore P. A role for CBFbeta in maintaining the metastatic phenotype of breast cancer cells. Oncogene. 2020; 39: 2624–2637
Rooney N, Mason SM, McDonald L, Däbritz JHM, Campbell KJ, Hedley A, Howard S, Athineos D, Nixon C, Clark W, Leach JDG, Sansom OJ, Edwards J, Cameron ER, Blyth K RUNX1 is a driver of renal cell carcinoma correlating with clinical outcome Cancer Res. 2020;
Rudzka DA, Mason S, Neilson M, McGarry L, Kalna G, Hedley A, Blyth K, Olson MF. Selection of established tumour cells through narrow diameter micropores enriches for elevated Ras/Raf/MEK/ERK MAPK signalling and enhanced tumour growth. Small GTPases. 2020;12:4, 294-310
Sweeney K, Cameron ER, Blyth K. Complex Interplay between the RUNX Transcription Factors and Wnt/β-Catenin Pathway in Cancer: A Tango in the Night. Molecules and cells. 2020; 43: 188-197
2019
Hassan S, Purdie KJ, Wang J, Harwood CA, Proby CM, Pourreyron C, Mladkova N, Nagano A, Dhayade S, Athineos D, Caley M, Mannella V, Blyth K, Inman GJ, Leigh IM. A Unique Panel of Patient-Derived Cutaneous Squamous Cell Carcinoma Cell Lines Provides a Preclinical Pathway for Therapeutic Testing. International journal of molecular sciences. 2019; 20: 3428
Johnson SA, Ormsby MJ, McIntosh A, Tait SWG, Blyth K, Wall DM. Increasing the bactofection capacity of a mammalian expression vector by removal of the f1 ori. Cancer Gene Ther. 2019; 26: 183–194
Liko D, Mitchell L, Campbell KJ, Ridgway RA, Jones C, Dudek K, King A, Bryson S, Stevenson D, Blyth K, Strathdee D, Morton JP, Bird TG, Knight JRP, Willis AE, Sansom OJ. Brf1 loss and not overexpression disrupts tissues homeostasis in the intestine, liver and pancreas. Cell Death Differ. 2019; 26: 2535–2550
Rudzka DA, Spennati G, McGarry DJ, Chim YH, Neilson M, Ptak A, Munro J, Kalna G, Hedley A, Moralli D, Green C, Mason S, Blyth K, Mullin M, Yin H, Olson MF. Migration through physical constraints is enabled by MAPK-induced cell softening via actin cytoskeleton re-organization. Journal of cell science. 2019; 132:
Vande Voorde J, Ackermann T, Pfetzer N, Sumpton D, Mackay G, Kalna G, Nixon C, Blyth K, Gottlieb E, Tardito S. Improving the metabolic fidelity of cancer models with a physiological cell culture medium. Science Advances 2019; 5: eaau7314
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; 9:19
McCarroll CS, He W, Foote K, Bradley A, McGlynn K, Vidler F, Nixon C, Nather K, Fattah C, Riddell A, Bowman P, Elliott EB, Bell M, Hawksby C, MacKenzie SM, et al. Runx1 Deficiency Protects Against Adverse Cardiac Remodeling After Myocardial Infarction. Circulation 2018; 137: 57-70.
Meiser J, Schuster A, Pietzke M, Vande Voorde J, Athineos D, Oizel K, Burgos-Barragan G, Wit N, Dhayade S, Morton JP, Dornier E, Sumpton D, Mackay GM, Blyth K, Patel KJ, et al. Increased formate overflow is a hallmark of oxidative cancer. Nat Commun. 2018; 9: 1368.
Novo D, Heath N, Mitchell L, Caligiuri G, MacFarlane A, Reijmer D, Charlton L, Knight J, Calka M, McGhee E, Dornier E, Sumpton D, Mason S, Echard A, Klinkert K, et al. Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels. Nat Commun 2018; 9: 5069.
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
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
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.
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
Morrissey B, Blyth K, Carter P, Chelala C, Jones L, Holen I, Speirs V. SEARCHBreast: a new online resource to make surplus material from in vivo models of breast cancer visible and accessible to researchers. Breast Cancer Res 2016;18: 59.
Group Members
Head
Karen Blyth
Karen.Blyth@glasgow.ac.uk
I did my PhD at the University of Glasgow (too long ago!) studying cancer biology and oncogenic mechanisms of key cancer genes using mouse models of cancer – an interest I have continued to pursue throughout my career and since joining the CRUK Scotland Institute in 2009. What I enjoy most about my job is the fantastic people I work with and exciting collaborative science we do. I also co-lead the MRC National Mouse Genetic Network (NMGN) Cancer Cluster which is a UK team using complex genetic models of cancer to understand tumour complexity and how these might be used for better prediction of patient response to therapy. When I can escape work, I am happiest spending time with friends and family, exploring new places, being on remote Scottish beaches or chasing down the Aurora Borealis!
Staff Scientist
Louise Mitchell
L.Mitchell@crukscotlandinstitute.ac.uk
I am a staff scientist based in the lab of Karen Blyth, which I joined at the end of 2022. My day-today job is primarily to assist Karen in managing her collaborative studies. I am originally from the island of Mauritius in the Indian Ocean. My journey in science began with my undergraduate studies in Science at the University of Queensland in Australia. This foundation fuelled my desire to explore the field further and broaden my horizons, so I moved to Scotland to complete my undergraduate studies and pursue a Ph.D. at the University of Glasgow. Outside of my professional life, I am a sports enthusiast and enjoy outdoor activities like hiking, swimming, cycling, and tennis. I also enjoy cooking, watching series and movies, and exploring nature. Family is incredibly important to me, and I cherish the time I spend with my loved ones.
Principal Scientific Officer
Dimitris Athineos
D.Athineos@crukscotlandinstitute.ac.uk
I am the lab’s Principal Scientific Officer and have been at the Institute since 2005, first as a post-doc, after obtaining my Ph.D. from the University of Glasgow, and then as scientific officer. I have a diverse range of responsibilities, but my main expertise is in vivo models of cancer, having worked with a number of them over the years. I also collaborate with and provide support to other groups at the Institute for their in vivo work, as well as help with day-to-day running of the lab. In my downtime, I enjoy gaming and recently rediscovered my appreciation for live music (of the heavy variety).
Senior Scientific Officers
Jayanthi Anand
J.Anand@crukscotlandinstitute.ac.uk
As a Senior Scientific Officer, I focus on in vivo cancer models and IVIS imaging for studying cancer growth and treatment responses. My responsibilities include using advanced imaging techniques to monitor tumour progression and treatment outcomes in real-time. Prior to joining CRUK, I completed my Ph.D. in cancer biology at the University of Freiburg, Germany. I also gained experience as a postdoctoral fellow at the Friedrich Miescher Institute in Basel, Switzerland, and at the Tumour Biology Center in Freiburg. At CRUK, I collaborate with teams both within the institute and across the UK to advance new cancer treatments. We use preclinical models to understand how potential therapies might work in patients. In my free time, I find joy in baking, cooking, dancing, and exploring nature, which helps me relax and stay happy.
Laura Galbraith
L.Galbraith@crukscotlandinstitute.ac.uk
I am one of the Senior Scientific officers in the lab, I joined the lab in 2020 to follow my interest in in vivo modelling of cancer. My role is to support the day to day activities of the lab and researchers, involvement in collaborative projects both within the institute and externally, as well as perusing my own research focusing on the role of Runx2 breast and prostate cancer. I have been at the CRUK Scotland Institute since beginning my PhD in 2009, with a brief hiatus in 2014 when I travelled to Australia for a year to work in the Walter and Eliza hall Institute in Melbourne. Outside of the lab my interests lie in outdoor activities, particularly those involving being on or in the water; sailing, surfing, stand-up paddle boarding and swimming. I also enjoy travelling and visiting new places, particularly places with good food to try!
Dale Watt
D.Watt@crukscotlandinstitute.ac.uk
I am a Senior Scientific Officer within the lab working predominantly on in vivo models of cancer. I work as part of the National Mouse Genetics Network in the Cancer Cluster group where we aim to develop and improve in vivo cancer models in order to align these better with human disease. I obtained my PhD at the CRUK Scotland institute in the field of Pancreatic Cancer and have an honours degree in Immunology from the University of Glasgow.