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.
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
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
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
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
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
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
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
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