Transgenic Models of Cancer
Professor Karen Blyth
Head 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 Beatson 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 Beatson 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.
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.
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.
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;10.1002/1878-0261.12734.
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;10.1080/21541248.2020.1780108:1-17.
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
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
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.
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
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.