Title

Nicholas La Thangue

Cancer Cell Cycle Group

Research in Nick La Thangue’s group focusses on the mechanisms that give rise to the abnormal proliferation characteristic of tumour cells.

Email: 
nick.lathangue@oncology.ox.ac.uk
Telephone: 
+44 (0)1865 617090/+44 (0)1865 617997
PA: 
Tuija Vanittnen-Newton
Email PA: 
tuija.vanttinen-newton@oncology.ox.ac.uk
College: 
Linacre College

Research Summary

An underpinning theme of our studies is that we believe, in order to design better therapies that effectively treat cancer, it is essential to decipher the molecular and biological details of pathways that control proliferation in normal cells and thereafter understand how they become aberrant in cancer.

A hallmark of tumour cells is evident in the control of the G1 to S phase transition; in normal cells this transition is tightly regulated whereas tumour cells progress liberally into S phase in an unrestrained fashion. There are two key pathways of pivotal importance that govern progress through G1 into S phase, controlled by the retinoblastoma tumour suppressor protein pRb and the p53 tumour suppressor protein. pRb principally acts as a transcriptional regulator of the E2F family of cell cycle regulating transcription factors. In contrast, p53 is a stress-responsive transcription factor that activates genes involved with cell cycle arrest and apoptosis. Most tumour cells harbour mutations that alter pRb and p53 activity. Loss of pRb results in deregulated proliferation as a consequence of liberating E2F activity, whereas loss of p53 causes an insensitivity to checkpoint control.

The primary objective of our work is to explore the regulation of and control by pRb and p53 activity.  Specifically, we have defined new levels of control in regulating pRb tumour suppressor activity, particularly novel post-translational signals. We have elucidated new members of the E2F family, and identified the key pathways through which they act.  Functional characterisation of E2F in cell cycle control and apoptosis has identified a remarkable level of complexity that governs the switch to apoptosis.  Our p53 research is principally focused on uncovering the diverse modifications that dictate the outcomes of the p53 response to stress.

We believe that biological knowledge on the mechanisms which drive cancer cell proliferation can be harnessed in designing new therapeutic modalities to treat cancer. Consequently, we work closely with the bio-technology and pharmaceutical sectors, together with clinical colleagues in translating our academic discoveries into an applied clinical setting. Drugs emanating from our earlier studies have been approved for haematological malignancy.

A major focus of our current work is to develop technologies that enable predictive biomarkers to be identified for cancer therapies. We have devised a genome-wide loss-of-function screen that identifies predictive biomarkers and deployed the platform to develop companion diagnostic tests for diverse cancer drugs.

Projects

Project code: ONC18NLT1
Supervisor: Nicholas La Thangue

Biography

Nicholas La Thangue is Professor of Cancer Biology in the Department of Oncology, and was previously Cathcart Professor of Biochemistry at the University of Glasgow, and before that a scientist at the Medical Research Council. He is a Fellow of the Royal Society of Edinburgh, a Member of the European Molecular Biology Organisation (EMBO), a Fellow of the Academy of Medical Sciences, a Fellow of the European Academy of Cancer Sciences, a Fellow of the Lister Institute and Professorial Fellow at Linacre College Oxford. He has founded several biotech companies, most recently Oxford Cancer Biomarkers.

Publications

SELECTED PUBLICATIONS:

Munro, S., Hookway, E. S., Floderer, M., Carr, S. M., Konietzny, R., Kessler, B. M., La Thangue, N. B. (2017). Linker Histone H1.2 Directs Genome-wide Chromatin Association of the Retinoblastoma Tumor Suppressor Protein and Facilitates Its Function. Cell Rep, 19(11), 2193-2201. doi:10.1016/j.celrep.2017.05.053

Olzscha, H., Fedorov, O., Kessler, B. M., Knapp, S., & La Thangue, N. B. (2017). CBP/p300 Bromodomains Regulate Amyloid-like Protein Aggregation upon Aberrant Lysine Acetylation. Cell Chem Biol, 24(1), 9-23. doi:10.1016/j.chembiol.2016.11.009

New, M., Sheikh, S., Bekheet, M., Olzscha, H., Thezenas, M. L., Care, M. A., La Thangue, N. B. (2016). TLR Adaptor Protein MYD88 Mediates Sensitivity to HDAC Inhibitors via a Cytokine-Dependent Mechanism. Cancer Res, 76(23), 6975-6987. doi:10.1158/0008-5472.CAN-16-0504

Kawalkowska, J., Quirke, A. M., Ghari, F., Davis, S., Subramanian, V., Thompson, P. R., Williams, R., Fisher, R., La Thangue, N.B., Venables, P. J. (2016). Abrogation of collagen-induced arthritis by a peptidyl arginine deiminase inhibitor is associated with modulation of T cell-mediated immune responses.  Scientific Reports, 6, 26430.

Ghari, F., Quirke, A. M., Munro, S., Kawalkowska, J., Picaud, S., McGouran, J., La Thangue, N. B. (2016). Citrullination-acetylation interplay guides E2F-1 activity during the inflammatory response. Science Advances, 2(2), e1501257.

Coutts, A. S., & La Thangue, N. B. (2015). Actin nucleation by WH2 domains at the autophagosome. Nature Communications, 6, 7888.

Carr, S. M., Munro, S., Zalmas, L. P., Fedorov, O., Johansson, C., Krojer, T., La Thangue, N. B. (2014). Lysine methylation-dependent binding of 53BP1 to the pRb tumor suppressor. Proceedings of the National Academy of Sciences of the United States of America, 111(31), 11341-11346.

Zheng, S., Moehlenbrink, J., Lu, Y.C., Zalmas, L.P., Sagum, C.A., Carr, S., McGouran, J.F., Alexander, L., Fedorov, O., Munro, S., Kessler, B., Bedford, M.T., Yu, Q. and La Thangue, N.B. (2013) Arginine methylation-dependent reader-writer interplay governs growth control by E2F-1. Molecular Cell, 52 (1) 37-51

Cho, E-C., Zheng, S., Munro, S., Liu, G., Stimson, S., Khan, O., Carr, S., Lu, Y-C., Coutts, A.S., Kerr, D.J. and La Thangue, N.B. (2012) Arginine methylation controls growth regulation by E2F-1. EMBO Journal, 31: 1785-1797.

Associated Researchers

Group Members

Mina Bekheet, DPhil Student
Simon Carr, Postdoctoral Researcher
Fatemeh Ghari, DPhil Student
Rebecca Miller, Postdoctoral Researcher
Jutta Moelenbrink, Postdoctoral Researcher
Shonagh Munro, Postdoctoral Researcher
Heidi Olzscha, Postdoctoral Researcher
Poppy Roworth, DPhil Student

Collaborators

Professor Rene Bernards, Netherlands
Dr Chas Bountra, Oxford
Professor Madeline Duvic, Texas
Professor Adrian Harris, Oxford
Professor David Kerr, Oxford
Dr Rachel Kerr, Oxford
Dr Benedict Kessler, Oxford
Professor Stefan Knapp, Oxford
Professor Mark Middleton, Oxford
Professor Udo Opperman, Oxford
Professor Francesco Pezzella, Oxford

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