Transgenic Technology
Introduction
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Dr Douglas StrathdeeHead of Transgenic Technology Facility |
During the development of cancer, cells frequently lose attributes of their tissue of origin and acquire some of the characteristics of stem cells, a process termed anaplasia. The aim of the research in our lab is to use stem cells to model the processes underlying cancer and to uncover the roles that novel stem cell and reprogramming factors play in the development of the disease. Using embryonic stem (ES) cells we are developing and improving models of human cancer. The targeted genetic modification of such cells allows us to study genes involved in cancer in fine detail so as to better understand their normal function and how these functions are compromised during the development of cancer.
Once modified ES cell lines are established, not only can gene function be analysed in the stem cells themselves but these cells can be differentiated into a wide variety of different cell types to allow the study of basic disease mechanisms in different tissues and potentially to establish screens for drug discovery. In addition, it is possible to reverse the differentiation process and reprogramme a variety of somatic cells to induced pluripotential stem (iPS) cells. This process is reminiscent of anaplasia, the loss of differentiation seen in cancer. Genes crucial for this type of reprogramming are often involved in cancer development.
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Lab Report
pdf Transgenic Technology Lab Report (88 KB)
Key Publications
Strathdee D, Whitelaw CB, Clark AJ. Distal transgene insertion affects CpG island maintenance during differentiation. J Biol Chem. 283, 11509-15, 2008
Strathdee D, Ibbotson H, Grant SG. Expression of transgenes targeted to the Gt(ROSA)26Sor locus is orientation dependent. PLoS One 1, e4, 2006
Brown K, Strathdee D, Bryson S, Lambie W, Balmain A. The malignant capacity of skin tumours induced by expression of a mutant H-ras transgene depends on the cell type targeted. Curr Biol. 8, 516-24, 1998
Recent Publications
2024
Najumudeen AK, Fey SK, Millett LM, Ford CA, Gilroy K, Gunduz N, Ridgway RA, Anderson E, Strathdee D, Clark W, Nixon C, Morton JP, Campbell AD, Sansom OJ. KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo. Nat Commun. 2024;15(1):100.
Whyte D, Voorde JV, Sumpton D, Dhayade S, Dornier E, Moore M, Novo D, Peters J, Wiesheu R, Mackey JBG, McFarlane AJ, Fercoq F, Fisher S, Caballero CD, Gilroy K, Redmond KL, Mitchell LE, Anderson E, Thomson G, Dzierozynski LN, Saab JJA, Lewis CA, Muir A, Halbrook CJ, Strathdee D, Jackstadt R, Nixon C, Dunne P, Steele CW, Carlin LM, Macpherson IR, Roberts EW, Coffelt SB, Blyth K, Sansom OJ, Norman JC, Clarke CJ. Uridine Phosphorylase-1 supports metastasis of mammary cancer by altering immune and extracellular matrix landscapes of the lung. bioRxiv. 2024:2024.2007.2002.601676.
2023
Hennequart M, Pilley SE, Labuschagne CF, Coomes J, Mervant L, Driscoll PC, Legrave NM, Lee Y, Kreuzaler P, Macintyre B, Panina Y, Blagih J, Stevenson D, Strathdee D, Schneider-Luftman D, Grönroos E, Cheung EC, Yuneva M, Swanton C, Vousden KH. ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis. Cell Rep. 2023;42:112562.
Moore M, Pardo L, Mitchell L, Schmidt T, May S, Mueller M, Strathdee D, Bryson S, Hodge K, Lilla S, Zanivan S, Waldron J, McGarry L, Peter-Durairaj R, Kanellos G, Nixon C, Ballantyne F, LeQuesne J, Sansom OJ, Bird T, Bushell M, Norman JC. The eIF4A2 negative regulator of mRNA translation promotes extracellular matrix deposition to accelerate hepatocellular carcinoma initiation. bioRxiv. 2023;Volume:2023.2008.2016.553544.
Perera G, Power L, Larson A, Codden CJ, Awata J, Batorsky R, Strathdee D, Chin MT. Single Cell Transcriptomic Analysis in a Mouse Model of Barth Syndrome Reveals Cell-Specific Alterations in Gene Expression and Intercellular Communication. Int J Mol Sci. 2023;24:11594
Tomczewski MV, Chan JZ, Campbell ZE, Strathdee D, Duncan RE. Phenotypic Characterization of Male Tafazzin-Knockout Mice at 3, 6, and 12 Months of Age. Biomedicines. 2023;11:638
Wang S, Yazawa E, Keating E, Mazumdar N, Hauschild A, Ma Q, Wu H, Xu Y, Shi X, Strathdee D, Gerszten RE, Schlame M, Pu WT. Genetic modifiers modulate phenotypic expression of tafazzin deficiency in a mouse model of Barth syndrome. Hum Mol Genet. 2023;32:2055–2067
2022
Baudot AD, Wang VM, Leach JD, O'Prey J, Long JS, Paulus-Hock V, Lilla S, Thomson DM, Greenhorn J, Ghaffar F, Nixon C, Helfrich MH, Strathdee D, Pratt J, Marchesi F, Zanivan S, Ryan KM. Glycan degradation promotes macroautophagy. Proc Natl Acad Sci U S A. 2022;119(26):e2111506119.
Flanagan DJ, Amirkhah R, Vincent DF, Gundaz N, Gentaz P, Cammareri P, McCooey AJ, McCorry AMB, Fisher NC, Davis HL, Ridgway RA, Lohuis J, Leach JDG, Jackstadt R, Gilroy K, Mariella E, Nixon C, Clark W, Hedley A, Markert EK, Strathdee D, Bartholin L, Redmond KL, Kerr EM, Longley DB, Ginty F, Cho S, Coleman HG, Loughrey MB, Bardelli A, Maughan TS, Campbell AD, Lawler M, Leedham SJ, Barry ST, Inman GJ, van Rheenen J, Dunne PD, Sansom OJ. Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features. Nat Commun. 2022;13:7551.
Humpton TJ, Hock AK, Kiourtis C, De Donatis M, Fercoq F, Nixon C, Bryson S, Strathdee D, Carlin LM, Bird TG, Blyth K, Vousden KH. A noninvasive iRFP713 p53 reporter reveals dynamic p53 activity in response to irradiation and liver regeneration in vivo. Sci Signal. 2022;15:eabd9099.
2021
Gudiño V, Pohl S, Billard CV, Cammareri P, Bolado A, Aitken S, Stevenson D, Hall AE, Agostino M, Cassidy J, Nixon C, von Kriegsheim A, Freile P, Popplewell L, Dickson G, Murphy L, Wheeler A, Dunlop M, Din F, Strathdee D, Sansom OJ, Myant KB. RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways. Nat Commun. 2021;12:2335.
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.
Julian L, Naylor G, Wickman GR, Rath N, Castino G, Stevenson D, Bryson S, Munro J, McGarry L, Mullin M, Rice A, Del Río Hernández A, Olson MF. Defective apoptotic cell contractility provokes sterile inflammation, leading to liver damage and tumour suppression. eLife. 2021;10:e61983.
Leach JDG, Vlahov N, Tsantoulis P, Ridgway RA, Flanagan DJ, Gilroy K, Sphyris N, Vázquez EG, Vincent DF, Faller WJ, Hodder MC, Raven A, Fey S, Najumudeen AK, Strathdee D, Nixon C, Hughes M, Clark W, Shaw R, van Hooff SR, Huels DJ, Medema JP, Barry ST, Frame MC, Unciti-Broceta A, Leedham SJ, Inman GJ, Jackstadt R, Thompson BJ, Campbell AD, Tejpar S, Sansom OJ. Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis. Nat Commun. 2021;12:3464.
Najumudeen AK, Ceteci F, Fey SK, Hamm G, Steven RT, Hall H, Nikula CJ, Dexter A, Murta T, Race AM, Sumpton D, Vlahov N, Gay DM, Knight JRP, Jackstadt R, Leach JDG, Ridgway RA, Johnson ER, Nixon C, Hedley A, et al. The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer. Nat Genet. 2021;53:16-26.
Pickering KA, Gilroy K, Cassidy JW, Fey SK, Najumudeen AK, Zeiger LB, Vincent DF, Gay DM, Johansson J, Fordham RP, Miller B, Clark W, Hedley A, Unal EB, Kiel C, McGhee E, Machesky LM, Nixon C, Johnsson AE, Bain M, et al. A RAC-GEF network critical for early intestinal tumourigenesis. Nat Commun. 2021;12:56.
Swaminathan K, Campbell A, Papalazarou V, Jaber-Hijazi F, Nixon C, McGhee E, Strathdee D, Sansom OJ, Machesky LM. The RAC1 Target NCKAP1 Plays a Crucial Role in the Progression of Braf;Pten-Driven Melanoma in Mice. J Invest Dermatol. 2021;141(3):628-637.e615.
2020
Corrado M, Edwards-Hicks J, Villa M, Flachsmann LJ, Sanin DE, Jacobs M, Baixauli F, Stanczak M, Anderson E, Azuma M, Quintana A, Curtis JD, Clapes T, Grzes KM, Kabat AM, Kyle R, Patterson AE, Geltink RK, Amulic B, Steward CG, Strathdee D, Trompouki E, O'Sullivan D, Pearce EJ, Pearce EL. Dynamic Cardiolipin Synthesis Is Required for CD8(+) T Cell Immunity. Cell Metab. 2020;32(6):981-995.e987.
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
Nobis M, Herrmann D, Warren SC, Strathdee D, Cox TR, Anderson KI, Timpson P. Shedding new light on RhoA signalling as a drug target in vivo using a novel RhoA-FRET biosensor mouse. Small GTPases. 2020;11(4):240-247.
Swaminathan K, Campbell A, Papalazarou V, Jaber-Hijazi F, Nixon C, McGhee E, Strathdee D, Sansom OJ, Machesky LM. The RAC1 target NCKAP1 plays a crucial role in progression of BRAF/PTEN -driven melanoma in mice. J Invest Dermatol. 2020:628-637.e15
Wang S, Li Y, Xu Y, Ma Q, Lin Z, Schlame M, Bezzerides VJ, Strathdee D, Pu WT. AAV Gene Therapy Prevents and Reverses Heart Failure in A Murine Knockout Model of Barth Syndrome. Circulation research. 2020;126:1024–1039
2019
Christodoulou N, Weberling A, Strathdee D, Anderson KI, Timpson P, Zernicka-Goetz M. Morphogenesis of extra-embryonic tissues directs the remodelling of the mouse embryo at implantation. Nature communications. 2019;10:3557.
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
Ren M, Xu Y, Erdjument-Bromage H, Donelian A, Phoon CKL, Terada N, Strathdee D, Neubert TA, Schlame M. Extramitochondrial cardiolipin suggests a novel function of mitochondria in spermatogenesis. J Cell Biol. 2019; 218 (5): 1491–1502
Schmidt S, Gay D, Uthe FW, Denk S, Paauwe M, Matthes N, Diefenbacher ME, Bryson S, Warrander FC, Erhard F, Ade CP, Baluapuri A, Walz S, Jackstadt R, Ford C, Vlachogiannis G, Valeri N, Otto C, Schulein-Volk C, Maurus K, Schmitz W, Knight JRP, Wolf E, Strathdee D, Schulze A, Germer CT, Rosenwald A, Sansom OJ, Eilers M, Wiegering A. A MYC-GCN2-eIF2alpha negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer. Nature cell biology. 2019; 21: 1413–1424
2018
Konjar S, Frising UC, Ferreira C, Hinterleitner R, Mayassi T, Zhang Q, Blankenhaus B, Haberman N, Loo Y, Guedes J, Baptista M, Innocentin S, Stange J, Strathdee D, Jabri B, et al. Mitochondria maintain controlled activation state of epithelial-resident T lymphocytes. Sci Immunol 2018;3(24): eaan2543
Lou W, Reynolds CA, Li Y, Liu J, Huttemann M, Schlame M, Stevenson D, Strathdee D, Greenberg ML. Loss of tafazzin results in decreased myoblast differentiation in C2C12 cells: A myoblast model of Barth syndrome and cardiolipin deficiency. Biochim Biophys Acta 2018;1863(8):857-65.
Nobis M, Herrmann D, Warren SC, Strathdee D, Cox TR, Anderson KI, Timpson P. Shedding new light on RhoA signalling as a drug target in vivo using a novel RhoA-FRET biosensor mouse. Small GTPases 2018:1-8.
Warren SC, Nobis M, Magenau A, Mohammed YH, Herrmann D, Moran I, Vennin C, Conway JR, Melenec P, Cox TR, Wang Y, Morton JP, Welch HC, Strathdee D, Anderson KI, et al. Removing physiological motion from intravital and clinical functional imaging data. Elife 2018;7: e35800
Woroniuk A, Porter A, White G, Newman DT, Diamantopoulou Z, Waring T, Rooney C, Strathdee D, Marston DJ, Hahn KM, Sansom OJ, Zech T, Malliri A. STEF/TIAM2-mediated Rac1 activity at the nuclear envelope regulates the perinuclear actin cap. Nat Commun 2018;9(1):2124
2017
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
Nobis M, Herrmann D, Warren SC, Kadir S, Leung W, Killen M, Magenau A, Stevenson D, Lucas MC, Reischmann N, Vennin C, Conway JRW, Boulghourjian A, Zaratzian A, Law AM, Gallego-Ortega D, Ormandy CJ, Walters SN, Grey ST, Bailey J et al. A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts. Cell Rep 2017; 21: 274-88
van de Lagemaat LN, Stanford LE, Pettit CM, Strathdee DJ, Strathdee KE, Elsegood KA, Fricker DG, Croning MD, Komiyama NH, Grant SG. Standardized experiments in mutant mice reveal behavioural similarity on 129S5 and C57BL/6J backgrounds. Genes Brain Behav 2017; 16: 409-18
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;
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;76(20):6118-6129
