Lindsay Spender

Postdoctoral Research Assistant

Biography

Lindsay graduated from The University of Birmingham, U.K. before working in the pharmaceutical industry for four years helping to identify novel anti-viral therapeutic agents. She was then accepted on the Welcome Prize Studentship programme to study for a PhD in immunology at Imperial College, London, where she carried out research into the pathological effects of a common childhood respiratory virus. Lindsay then joined Professor Paul Farrell’s laboratory in the Ludwig Institute for Cancer Research, London as a postdoctoral scientist working on Epstein-Barr virus. There she developed a long term interest in B-cell biology, lymphomas and cancer. Lindsay joined Gareth’s laboratory at The Beatson Institute for Cancer Research in Glasgow in 2004 to study the mechanisms of TGF-beta induced tumour suppressor activity in human B cells and B cell lymphomas. She has continued as senior postdoctoral scientist in Gareth’s following the move to Dundee. Lindsay’s work is supported by the AICR.

Research

TGF-beta has a vital role in protection against developing cancer through its tumour suppressor activity. This can be attributed to its potent ability to arrest cell proliferation and through its induction of programmed cell death (apoptosis). I have been interested in studying the mechanisms of TGF? tumour suppressor activity. One of the best model systems in which to study this aspect of TGF-beta biology is in normal primary human B cells and Burkitt’s Lymphoma (BL) cell lines.

Our detailed molecular analyses of this model system has revealed that TGF beta signalling acts as a central regulator of centroblastic B cell apoptosis via co-ordinated regulation of the BCL2 family of cell death and survival proteins (Spender et al., CDD 2009, Spender et al JBC 2013). Based upon these studies and those of others we have investigated the potential of targeting survival pathway signalling as a therapeutic target in B cell malignancies (Spender and Inman, Expert Opinion Ther. Targets 2009a) and have discovered that dual targeting of the pro-survival BCL2 family and the PI3K/mTOR pathway may be a valuable approach for lymphoma management (Spender and Inman, Mol. Cancer Res, 2012). We have also revealed novel pathways of cytostasis in B cells (Spender and Inman, JBC 2009). Our current studies have expanded to investigate how TGF beta signalling may regulate melanoma cell survival.

Publications

Spender LC, Inman GJ. Developments in Burkitt's lymphoma: novel cooperations in oncogenic MYC signaling. Cancer Manag Res. 2014 Jan 9;6:27-38. Review.

Spender LC, Carter MJ, O'Brien DI, Clark LJ, Yu J, Michalak EM, Happo L, Cragg MS, Inman GJ. Transforming growth factor-? directly induces p53-up-regulated modulator of apoptosis (PUMA) during the rapid induction of apoptosis in myc-driven B-cell lymphomas. J Biol Chem. 2013 Feb 15;288(7):5198-209. doi: 10.1074/jbc.M112.410274. Epub 2012 Dec 14.

Spender LC, Inman GJ. Phosphoinositide 3-kinase/AKT/mTORC1/2 signaling determines sensitivity of Burkitt's lymphoma cells to BH3 mimetics. Mol Cancer Res. 2012 Mar;10(3):347-59. doi: 10.1158/1541-7786.MCR-11-0394. Epub 2012 Jan 12.

Spender LC, Inman GJ. Inhibition of germinal centre apoptotic programmes by epstein-barr virus. Adv Hematol. 2011;2011:829525. doi: 10.1155/2011/829525. Epub 2011 Oct 23.

Hannigan A, Smith P, Kalna G, Lo Nigro C, Orange C, O'Brien DI, Shah R, Syed N, Spender LC, Herrera B, Thurlow JK, Lattanzio L, Monteverde M, Maurer ME, Buffa FM, Mann J, Chu DC, West CM, Patridge M, Oien KA, Cooper JA, Frame MC, Harris AL, Hiller L, Nicholson LJ, Gasco M, Crook T, Inman GJ. Epigenetic downregulation of human disabled homolog 2 switches TGF-beta from a tumor suppressor to a tumor promoter. J Clin Invest. 2010 Aug 2;120(8):2842-57. doi: 10.1172/JCI36125. Epub 2010 Jul 1.

Spender LC, Inman GJ. Targeting the BCL-2 family in malignancies of germinal centre origin. Expert Opinion on Therapeutic Targets. 2009 Dec;13(12):1459-72.

Brady G, Whiteman HJ, Spender LC, Farrell PJ. Downregulation of RUNX1 by RUNX3 requires the RUNX3 VWRPY sequence and is essential for Epstein-Barr virus-driven B-cell proliferation. J Virol. 2009 Jul;83(13):6909-16. Epub 2009 Apr 29.

Spender LC, O’Brien DI, Simpson D, Dutt D, Gregory CD, Allday MJ, Clark LJ, Inman GJ. TGF-beta induces apoptosis in human B cells by transcriptional regulation of BIK and BCL-X(L). Cell Death and Differentiation. 2009 Apr;16(4):593-602. Epub 2009 Jan 9.

Fleming YM, Ferguson GJ, Spender LC, Larsson J, Karlsson S, Ozanne BW, Grosse R, Inman GJ. TGF-beta-mediated activation of RhoA signalling is required for efficient (V12)HaRas and (V600E)BRAF transformation. Oncogene. 2009 Feb19;28(7):983-9. Epub 2008 Dec15.

Spender LC, Inman GJ. TGF-beta induces growth arrest in Burkitt's lymphoma cells via transcriptional repression of E2F-1. Journal of Biological Chemistry. 2009 Jan 16;284(3): 1435-42. Epub 2008 Dec 15.

Spender LC, Lucchesi W, Bodelon G, Bilancio A, Karstegl CE, Asano T, Dittrich-Breiholz O, Kracht M, Vanhaesebroeck B, Farrell PJ. Cell target genes of Epstein-Barr virus transcription factor EBNA-2: induction of the p55alpha regulatory subunit of PI3-kinase and its role in survival of EREB2.5 cells. Journal of General Virology. 2006 Oct;87(Pt 10):2859-67.

Syed N, Smith P, Sullivan A, Spender LC, Dyer M, Karran L, O'Nions J, Allday M, Hoffmann I, Crawford D, Griffin B, Farrell PJ, Crook T. Transcriptional silencing of Polo-like kinase 2 (SNK/PLK2) is a frequent event in B-cell malignancies. Blood. 2006 Jan 1;107(1):250-6. Epub 2005 Sep 13.

Spender LC, Whiteman HJ, Elgueta Karsteg C, Farrell PJ. Transcriptional cross-regulation of RUNX1 by RUNX3 in human B cells. Oncogene 2005 Mar 10;24(11):1873-81.

De Jesus O, Smith PR, Spender LC, Elgueta Karstegl C, Niller HH, Huang D, Farrell PJ. Updated Epstein-Barr virus (EBV) DNA sequence and analysis of a promoter for the BART (CST, BARF0) RNAs of EBV. Journal of General Virology, 2003 84(6) 1443-1450.

Spender L.C., Cornish G.H., Sullivan A. and Farrell P.J. Expression of the transcription factor AML-2 (RUNX-3, CBFa-3) is induced by Epstein-Barr Virus EBNA-2 and correlates with the B cell activation phenotype. Journal of Virology 2002 76(10), 4919-4927

Spender L.C., Cornish G.H., Rowland B., Kempkes B., and Farrell P.J. Direct and Indirect Regulation of Cytokine and Cell Cycle Proteins by EBNA-2 during Epstein-Barr Virus Infection. Journal of Virology 2001 75(8), 3537-3546.

Spender L.C., Cannell E.J., Hollyoake M., Wensing B., Gawn J.M., Brimmell M., Packham G. and Farrell P.J. Control of Cell Cycle Entry and Apoptosis in B lymphocytes Infected by Epstein-Barr Virus. Journal of Virology 1999 73(6), 4678-4688.

Spender L.C., Hussell T. and Openshaw P.J.M. Abundant IFN-gamma production by local T cells in respiratory syncytial virus-induced eosinophilic lung disease. Journal of General Virology 1998 79, 1751-1758.

Openshaw P.J.M., Sparer T., Spender L., Mathews S., Pala P. and Hussell T. Investigative measures for airway inflammation: viruses and T-helper 2 responses. The European Respiratory Review 1998, 8, 1128.

Hussell T., Spender L.C., Georgiou A., O’Garra A and Openshaw P.J.M. Th4 and Th4 cytokine induction in pulmonary T-cells during infection with respiratory syncytial virus. Journal of General Virology 1996 77, 2447-2455.

Openshaw P.J.M., Spender L.C. and Hussell T. Beneficial and harmful immune responses in the respiratory tract. Essentials of Mucosal Immunology, 1996, Kagnoff and Kiyono, Academic Press, Chapter 32, 449-457.

Bacon T.H., Howard B.A., Spender L.C., and Boyd M.R. Activity of penciclovir in antiviral assays against herpes simplex virus. Journal of Antimicrobial Chemotherapy 1996 37, 303-313.