Michael Olson - Molecular Cell Biology

Introduction

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The Rho family of small molecular weight GTPases has emerged as a critically important group of signalling proteins in human cancer. In contrast to the closely related Ras GTPases that are relatively frequently activated by mutation, Rho family genes are not mutationally activated in cancers. However, research has revealed that signalling via Rho GTPase regulated pathways is intimately linked with a wide variety of biological processes that contribute to the initiation, growth and progression of human tumours. My lab has focussed on characterizing how these Rho GTPase signalling pathways contribute to cancer, with the ultimate goal of identifying critical elements that could be targeted with small molecule inhibitors.

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Our research efforts have been directed at three levels: understanding the fundamental molecular mechanisms by which Rho GTPases contribute to the regulation of proliferation, cell division and apoptosis/survival; creating mouse models to determine how Rho signalling promotes tumourigenesis and growth in vivo and for testing Rho signalling inhibitors as potential chemotherapeutic agents; initiating and driving drug discovery efforts that will lead to the development of novel inhibitors of Rho signalling pathway components.

By working at these multi-disciplinary levels, a powerful self-reinforcing package has been created. For example, drug discovery efforts have facilitated research at the fundamental level, while discoveries made using in vivo models have revealed potential new cancer drug targets. We will continue to work in all three areas, with particular focus on the ROCK, LIMK and MRCK kinases that act downstream of Rho GTPases.

Want to find out more about Professor Olson's work?

Read about his 2011 Cancer Cell paper on the CRUK science blog and listen to him talking about collagen scaffolding on YouTube.

Lab Report

Key Publications

Wickman GR, Julian L, Mardilovich K, Schumacher S, Munro J, Rath N, Zander SA, Mleczak A, Sumpton D, Morrice N, Bienvenut WV, Olson MF. Blebs produced by actin-myosin contraction during apoptosis release damage-associated molecular pattern proteins before secondary necrosis occurs. Cell Death Differ. 20, 1293-305, 2013

Klejnot M, Gabrielsen M, Cameron J, Mleczak A, Talapatra SK, Kozielski F, Pannifer A, Olson MF. Analysis of the human cofilin 1 structure reveals conformational changes required for actin binding. Acta Crystallogr D Biol Crystallogr. 69, 1780-8, 2013

Lourenço FC, Munro J, Brown J, Cordero J, Stefanatos R, Strathdee K, Orange C, Feller SM, Sansom OJ, Vidal M, Murray GI, Olson MF. Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. Gut doi:10.1136/gutjnl-2012-303883, published online 12 Apr 2013

Samuel MS, Lopez JI, McGhee EJ, Croft DR, Strachan D, Timpson P, Munro J, Schroder E, Zhou J, Brunton VG, Barker N, Clevers H, Sansom OJ, Anderson KI, Weaver VM, Olson MF. Actomyosin-mediated cellular tension drives increased tissue stiffness and beta-catenin activation to induce epidermal hyperplasia and tumor growth. Cancer Cell 19, 776-91, 2011

Scott RW, Hooper S, Crighton D, Li A, König I, Munro J, Trivier E, Wickman G, Morin P, Croft DR, Dawson J, Machesky L, Anderson KI, Sahai EA, Olson MF. LIM kinases are required for invasive path-generation by tumor and tumor-associated stromal cells. J Cell Biol. 191, 169-85, 2010

Biography

Education and qualifications

1993: PhD, University of Toronto, Supervisor Bernard Schimmer
1985: BSc, Genetics, University of Alberta

Appointments

2008-present: Deputy Postgraduate Convenor, Division of Cancer Sciences, University of Glasgow
2007-present: Professor of Molecular Oncology, University of Glasgow
2006-present: Senior Group Leader, CRUK Beatson Institute
2004-2006: Junior Group Leader, CRUK Beatson Institute
2001-2004: Assistant Investigator, Abramson Family Cancer Research Institute; Assistant Professor, Dept of Cancer Biology: Assistant Professor, Dept of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, USA
1998-2001: Mr and Mrs John Jaffe Donation University Research Fellow of The Royal Society, Institute of Cancer Research, London
1996-1998: Institute of Cancer Research Fellow with Chris Marshall, Institute of Cancer Research, London
1993-1996: Natural Sciences and Engineering Research Council of Canada Postdoctoral Research Fellow with Alan Hall, University College London

Current committee membership

European Union H2020-FETOPEN-2014-RIA Novel ideas for radically new technologies
European Union H2020- Marie Skłodowska-Curie actions - IF-2014-Individual Fellowships
European Union H2020- Marie Skłodowska-Curie actions - ITN-2014-Initial Training Networks
Academy of Finland Research Council for Health
West of Scotland Comprehensive Cancer Centre Clinical Trials Executive Committee
West of Scotland Comprehensive Cancer Centre In-House Trials Advisory Board

Recent Publications

2017

Zihni C, Vlassaks E, Terry S, Carlton J, Leung TKC, Olson M, Pichaud F, Balda MS, Matter K. An apical MRCK-driven morphogenetic pathway controls epithelial polarity. Nat Cell Biol 19: 1049-60, 2017Masre SF, Rath N, Olson MF, Greenhalgh DA. ROCK2/rasHa co-operation induces malignant conversion via p53 loss, elevated NF-κB and tenascin C-associated rigidity, but p21 inhibits ROCK2/NF-κB-mediated progression. Oncogene 36: 2529-42, 2017

Rath N, Morton JP, Julian L, Helbig L, Kadir S, McGhee EJ, Anderson KI, Kalna G, Mullin M, Pinho AV, Rooman I, Samuel MS, Olson MF. ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth. EMBO Mol Med 9: 198-218, 2017

2016

McGarry DJ, Shchepinova MM, Lilla S, Hartley RC, Olson MF. A cell-permeable biscyclooctyne as a novel probe for the identification of protein sulfenic acids. ACS Chem Biol 11: 3300-4, 2016

Rath N, Kalna G, Clark W, Olson MF. ROCK signalling induced gene expression changes in mouse pancreatic ductal adenocarcinoma cells. Sci Data  3: 160101, 2016

Samuel MS, Rath N, Masre SF, Boyle ST, Greenhalgh DA, Kochetkova M, Bryson S, Stevenson D, Olson MF. Tissue-selective expression of a conditionally-active ROCK2-estrogen receptor fusion protein. Genesis 54: 636-46, 2016

McGarry DJ, Olson MF. Coping with loss: Cell adaptation to cytoskeleton disruption. Dev Cell 39: 3-4, 2016

Olson MF. Rho GTPases, their post-translational modifications, disease-associated mutations and pharmacological inhibitors. Small GTPases 2016 Aug 12:1-13. [Epub ahead of print]

Rath N, Olson MF. Regulation of pancreatic cancer aggressiveness by stromal stiffening. Nat Med 22: 462-3, 2016

2015

Cameron JM, Gabrielsen M, Chim YH, Munro J, McGhee EJ, Sumpton D, Eaton P, Anderson KI, Yin H, Olson MF. Polarized Cell Motility Induces Hydrogen Peroxide to Inhibit Cofilin via Cysteine Oxidation. Curr Biol 2015; 25: 1520-5, 2015

Charles MD, Brookfield JL, Ekwuru CT, Stockley M, Dunn J, Pritchard M, Hammonds T, Trivier E, Greenland G, Wong AC, Cheasty A, Boyd S, Crighton D, Olson MF. Discovery, development and SAR of aminothiazoles as LIMK inhibitors with cellular anti-invasive properties. J Med Chem 2015; 58: 8309-13

Mardilovich K, Baugh M, Crighton D, Kowalczyk D, Gabrielsen M, Munro J, Croft DR, Lourenco F, James D, Kalna G, McGarry L, Rath O, Shanks E, Garnett MJ, McDermott U, Brookfield J, Charles M, Hammonds T, Olson MF. LIM kinase inhibitors disrupt mitotic microtubule organization and impair tumor cell proliferation. Oncotarget 2015. doi: 10.18632/oncotarget.6288. Epub 2015 Nov 3

Mardilovich K, Gabrielsen M, McGarry L, Orange C, Patel R, Shanks E, Edwards J, Olson MF. Elevated LIM kinase 1 in non-metastatic prostate cancer reflects its role in facilitating androgen receptor nuclear translocation. Mol Cancer Ther 14: 246-58, 2015

Rudzka DA, Cameron JM, Olson MF. Reactive oxygen species and hydrogen peroxide generation in cell migration. Commun Itegr Biol 2015, in press

Julian L, Olson MF. Apoptotic membrane dynamics in health and disease. Cell Health Cytoskelet 2015; 2015: 133-142

Rudzka DA, Olson MF. Microtrack migration: insights into 3D cell motility. Focus on "Comparative mechanisms of cancer cell migration through 3D matrix and physiological microtracks". Am J Physiol Cell Physiol 308: C434-5, 2015

2014

Julian L, Olson MF. Rho-associated coiled-coil containing kinases (ROCK): structure, regulation, and functions. Small GTPases 5: e29846, 2014

Prater MD, Petit V, Alasdair Russell I, Giraddi RR, Shehata M, Menon S, Schulte R, Kalajzic I, Rath N, Olson MF, Metzger D, Faraldo MM, Deugnier MA, Glukhova MA, Stingl J. Mammary stem cells have myoepithelial cell properties. Nat Cell Biol 16: 942-50, 2014

Unbekandt M, Croft DR, Crighton D, Mezna M, McArthur D, McConnell P, Schuttelkopf AW, Belshaw S, Pannifer A, Sime M, Bower J, Drysdale M, Olson MF. A novel small-molecule MRCK inhibitor blocks cancer cell invasion. Cell Commun Signal 12: 54, 2014

Unbekandt M, Olson MF. The actin-myosin regulatory MRCK kinases: regulation, biological functions and associations with human cancer. J Mol Med (Berl) 92: 217-25, 2014

2013

Gabrielsen M, Schuldt M, Munro J, Borucka D, Cameron J, Baugh M, Mleczak A, Lilla S, Morrice N, Olson MF. Cucurbitacin covalent bonding to cysteine thiols: the filamentous-actin severing protein Cofilin1 as an exemplary target. Cell Commun Signal 11: 58, 2013

Ibbetson SJ, Pyne NT, Pollard AN, Olson MF, Samuel MS. Mechanotransduction pathways promoting tumor progression are activated in invasive human squamous cell carcinoma. Am J Pathol 183: 930-7, 2013

Klejnot M, Gabrielsen M, Cameron J, Mleczak A, Talapatra SK, Kozielski F, Pannifer A, Olson MF. Analysis of the human cofilin 1 structure reveals conformational changes required for actin binding. Acta Crystallogr D Biol Crystallogr 69: 1780-8, 2013

Olson MF. Finding the shape-shifter genes. Nat Cell Biol 15: 723-5, 2013

Wickman GR, Julian L, Mardilovich K, Schumacher S, Munro J, Rath N, Zander SA, Mleczak A, Sumpton D, Morrice N, Bienvenut WV, Olson MF. Blebs produced by actin-myosin contraction during apoptosis release damage-associated molecular pattern proteins before secondary necrosis occurs. Cell Death Differ 20: 1293-305, 2013

Lourenço FC, Munro J, Brown J, Cordero J, Stefanatos R, Strathdee K, Orange C, Feller SM, Sansom OJ, Vidal M, Murray GI, Olson MF. Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. Gut doi:10.1136/gutjnl-2012-303883, published online 12 Apr 2013

Mleczak A, Millar S, Tooze SA, Olson MF and Chan EYW. Regulation of autophagosome formation by Rho kinase. Cell Signal 25: 1-11, 2013

2012

Mezna M, Wong AC, Ainger M, Scott RW, Hammonds T, Olson MF. Development of a high-throughput screening method for LIM kinase 1 using a luciferase-based assay of ATP consumption. J Biomol Screen 17: 460-8, 2012

Boomkamp S, Riehle M, Wood J, Olson MF, Barnett S. The development of a rat in vitro model of spinal cord injury demonstrating the additive effects of Rho and ROCK inhibitors on neurite outgrowth and myelination. Glia 60: 441-56, 2012

Jamieson T, Clarke M, Steele CW, Samuel MS, Neumann J, Jung A, Huels D, Olson MF, Das S, Nibbs RJB, and Sansom OJ. Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis in mice. J Clin Invest 122: 3127-44, 2012

Mardilovich K, Olson MF, Baugh M. Targeting Rho GTPase signaling for cancer therapy. Future Oncol 8: 165-77, 2012

Wickman G, Julian L, Olson MF. How apoptotic cells aid in the removal of their own cold dead bodies. Cell Death Differ 19: 735-42, 2012

Wood JM, Olson MF. Collective migration: spatial tension relief. Curr Biol 22: R125-7, 2012

Samuel MS and Olson MF. ROCK. In: Encyclopedia of Signalling Molecules. Choi, S. (Ed.): Springer, Heidelberg, 1686-1699, 2012

Rath N and Olson MF. Rho-associated kinases in tumorigenesis: re-considering ROCK inhibition for cancer therapy. EMBO Reports 13: 900-908, 2012

Lab Members

olson group

Post-docs

Steven Bryce
David McGarry (MRC)
Mathieu Unbekandt (Worldwide Cancer Research)

Scientific Officer

June Munro

Clinical Research Fellow

Greg Naylor

PhD Students

Narisa Phinichkusolchit
Dominika Rudzka

Former Lab Members

Felipe Lourenco, Post-doc, CRUK Cambridge Institute
Mark Baugh, Project Manager, Quintiles

Research

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Seminars

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Find out more about our seminars including our Distinguished Seminar Programme.

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