Robert Insall - Cell Migration and Chemotaxis

Introduction

insall r

Movement is a fundamental behaviour of cells and its regulation is particularly relevant to cancer because tumour invasion and metastasis are principal causes of death in cancer patients. Our group aims to understand how cell movement is regulated, using a mixture of genetics and microscopy. We are interested in several aspects of cell movement.

One is chemotaxis, in which external signals orient and attract cells, which is increasingly seen as a fundamental cause of metastasis. Metastasis, one of the most feared features of cancer, is caused when cells migrate out from a tumour into the blood, lymph or other tissues. Chemotaxis is clearly important in these processes but exactly how and why remain poorly understood.

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Another is the regulation of actin polymerization. Actin is the most abundant protein in eukaryotic cells. It polymerizes into filaments that provide the mechanical force needed to push cells forwards. It also has a number of other biological roles. We are most interested in actin's roles in cell movement and vesicle sorting. In cell movement, the SCAR/WAVE complex, a large multiprotein assembly, promotes movement through the formation of large pseudopods. In vesicles, a related multiprotein complex based around WASH causes actin to polymerize on vesicles, where it mediates sorting of different components within the cell.

We study these two processes in a range of different cells, particularly Dictyostelium and melanoma cells. Dictyostelium is an amoeba in which the genetic analysis of movement is especially straightforward, and it has been the best experimental organism for studying chemotaxis. Melanoma is a very dangerous and highly metastatic cancer. Its metastasis is derived from the rapid migration of its cells through tissue. We have recently shown that this migration is underpinned by remarkably accurate chemotaxis.

When experimentally appropriate, we also examine human neutrophils, tumour-derived cells, cultured mammalian cells or other amoebas such as Entamoeba (the cause of amoebic dysentery) – anything that will help us to understand the conserved and fundamental mechanisms that drive cell movement.

Lab Report

Key Publications

Park L, Thomason PA, Zech T, King JS, Veltman DM, Carnell M, Ura S, Machesky LM, Insall RH. Cyclical action of the WASH complex: FAM21 and capping protein drive WASH recycling, not initial recruitment. Dev Cell 24(2): 169-81, 2013

Veltman DM, King JS, Machesky LM, Insall RH. SCAR knockouts in Dictyostelium: WASP assumes SCAR's position and upstream regulators in pseudopods. J Cell Biol 198(4): 501-8, 2012

Ura S, Pollitt AY, Veltman DM, Morrice NA, Machesky LM, Insall RH. Pseudopod growth and evolution during cell movement is controlled through SCAR/WAVE dephosphorylation. Curr Biol 22(7): 553-61, 2012

Neilson MP, Veltman DM, van Haastert PJ, Webb SD, Mackenzie JA, Insall RH. Chemotaxis: a feedback-based computational model robustly predicts multiple aspects of real cell behaviour. PLoS Biol 9(5): e1000618, 2011

Insall RH. Understanding eukaryotic chemotaxis: a pseudopod-centred view. Nat Rev Mol Cell Biol 11(6): 453-8, 2010

Biography

Education and qualifications

1989: PhD, MRC Laboratory of Molecular Biology, Cambridge, Supervisor Rob Kay
1986: BA (Hons), Natural Sciences, University of Cambridge

Appointments

2007-present: Professor of Genetics and Cell Biology, University of Glasgow
2007-present: Group Leader, CRUK Beatson Institute, Glasgow
2005-2007: Professor of Molecular Cell Biology, University of Birmingham
2003-2005: Reader in Molecular Cell Biology, University of Birmingham
2000-2010: MRC Senior Non-clinical Fellow (renewed 2005)
1999-2007: Group Leader, School of Biosciences, University of Birmingham
1995-1998: Group Leader, MRC Laboratory for Molecular Cell Biology, London & Lecturer, Department of Physiology, University College London
1995-1999: Wellcome Trust Career Development Fellow
1992-1995: Postdoctoral Fellow, Johns Hopkins Medical School, Baltimore, USA
1991-1992: Research Officer, MRC Laboratory of Molecular Biology, Cambridge

Current committee membership

NC4Rs Grant Panel
Faculty of 1000

Honours and awards

Fellow of the Royal Society of Edinburgh, 2014

Recent Publications

2017

Periz J, Whitelaw J, Harding C, Gras S, Del Rosario Minina MI, Latorre-Barragan F, Lemgruber L, Reimer MA, Insall R, Heaslip A, Meissner M. Toxoplasma gondii F-actin forms an extensive filamentous network required for material exchange and parasite maturation. Elife 2017 Mar 21;6. pii: e24119. doi: 10.7554/eLife.24119

Thomason PA, King JS, Insall RH. Mroh1, a lysosomal regulator localised by WASH-generated actin. J Cell Sci 130: 1785-95, 2017

Woodham EF, Paul NR, Tyrrell B, Spence HJ, Swaminathan K, Scribner MR, Giampazolias E, Hedley A, Clark W, Kage F, Marston DJ, Hahn KM, Tait SW, Larue L, Brakebusch CH, Insall RH, Machesky LM. Coordination by Cdc42 of Actin, Contractility, and Adhesion for Melanoblast Movement in Mouse Skin. Curr Biol 27: 624-37, 2017

2016

Buckley CM, Gopaldass N, Bosmani C, Johnston SA, Soldati T, Insall RH, King JS. WASH drives early recycling from macropinosomes and phagosomes to maintain surface phagocytic receptors. Proc Natl Acad Sci USA 113: E5906-15, 2016

Ferguson EA, Matthiopoulos J, Insall RH, Husmeier D. Inference of the drivers of collective movement in two cell types: Dictyostelium and melanoma. J R Soc Interface 13: 20160695, 2016

Frej AD, Clark J, Le Roy CI, Lilla S, Thomason PA, Otto GP, Churchill G, Insall RH, Claus SP, Hawkins P, Stephens L, Williams RSB. The inositol-3-phosphate synthase biosynthetic enzyme has distinct catalytic and metabolic roles. Mol Cell Biol 36: 1464-79, 2016

Mackenzie JA, Nolan M, Insall RH. Local modulation of chemoattractant concentrations by single cells: dissection using a bulk-surface computational model. Interface Focus 6: 20160036, 2016

Tweedy L, Knecht DA, Mackay GM, Insall RH. Self-generated chemoattractant gradients: Attractant depletion extends the range and robustness of chemotaxis. PLoS Biol 14: e1002404, 2016

Tyrrell BJ, Woodham EF, Spence HJ, Strathdee D, Insall RH, Machesky LM. Loss of strumpellin in the melanocytic lineage impairs the WASH Complex but does not affect coat colour. Pigment Cell Melanoma Res 29: 559-71, 2016

Veltman DM, Williams TD, Bloomfield G, Chen BC, Betzig E, Insall RH, Kay RR. A plasma membrane template for macropinocytic cups. eLife 5: e20085, 2016

Susanto O, Muinonen-Martin AJ, Nobis M, Insall RH. Visualizing cancer cell chemotaxis and invasion in 2D and 3D. Methods Mol Biol 1407: 217-28, 2016

Tweedy L, Susanto O, Insall RH. Self-generated chemotactic gradients - cells steering themselves. Curr Opin Cell Biol 42: 46-51, 2016

2015

Roberts HM, Ling MR, Insall R, Kalna G, Spengler J, Grant MM, Chapple IL. Impaired neutrophil directional chemotactic accuracy in chronic periodontitis patients. J Clin Periodontol 42: 1-11, 2015

Siebert S, Machesky LM, Insall RH. Overflow in science and its implications for trust. Elife 2015. doi: 10.7554/eLife.10825. 4. Epub 2015 Sep 14

Urushihara H, Kuwayama H, Fukuhara K, Itoh T, Kagoshima H, Shin IT, Toyoda A, Ohishi K, Taniguchi T, Noguchi H, Kuroki Y, Hata T, Uchi K, Mohri K, King JS, Insall RH, Kohara Y, Fujiyama A. Comparative genome and transcriptome analyses of the social amoeba Acytostelium subglobosum that accomplishes multicellular development without germ-soma differentiation. BMC Genomics 16: 80, 2015

2014

Muinonen-Martin AJ, Susanto O, Zhang Q, Smethurst E, Faller WJ, Veltman DM, Kalna G, Lindsay C, Bennett DC, Sansom OJ, Herd R, Jones R, Machesky LM, Wakelam MJ, Knecht DA, Insall RH. Melanoma Cells Break Down LPA to Establish Local Gradients That Drive Chemotactic Dispersal. PLoS Biol 12: e1001966, 2014

Tyrrell BJ, Neilson M, Insall RH, Machesky LM. Predicting cell shapes in melanomas. Pigment Cell Melanoma Res 27: 5-6, 2014

Veltman DM, Lemieux MG, Knecht DA, Insall RH. PIP(3)-dependent macropinocytosis is incompatible with chemotaxis. J Cell Biol 204: 497-505, 2014

2013

Davidson AJ, King JS, Insall RH. The use of streptavidin conjugates as immunoblot loading controls and mitochondrial markers for use with Dictyostelium discoideum. Biotechniques 55: 39-41, 2013

Davidson AJ, Ura S, Thomason PA, Kalna G, Insall RH. Abi Is Required for Modulation and Stability but Not Localization or Activation of the SCAR/WAVE Complex. Eukaryot Cell 12: 1509-16, 2013

Insall R. The interaction between pseudopods and extracellular signalling during chemotaxis and directed migration. Curr Opin Cell Biol 25: 526-31, 2013

Insall RH. WASH complex conservation: don't WASH away the family! Trends Cell Biol, in press 2013

King JS, Gueho A, Hagedorn M, Gopaldass N, Leuba F, Soldati T, Insall RH. WASH is required for lysosomal recycling and efficient autophagic and phagocytic digestion. Mol Biol Cell 24: 2714-26, 2013

Muinonen-Martin AJ, Knecht DA, Veltman DM, Thomason PA, Kalna G, Insall RH. Measuring chemotaxis using direct visualization microscope chambers. Methods Mol Biol 1046: 307-21, 2013

Park L, Thomason PA, Zech T, King JS, Veltman DM, Carnell M, Ura S, Machesky LM, Insall RH. Cyclical action of the WASH complex: FAM21 and capping protein drive WASH recycling, not initial recruitment. Dev Cell 24: 169-81, 2013

Choi CH, Thomason PA, Zaki M, Insall RH, Barber DL. Phosphorylation of actin-related protein 2 (Arp2) is required for normal development and cAMP chemotaxis in Dictyostelium. J Biol Chem 288(4): 2464-74, 2013

Itakura A, Aslan JE, Kusanto BT, Phillips KG, Porter JE, Newton PK, Nan X, Insall RH, Chernoff J, McCarty OJ. p21-Activated kinase (PAK) regulates cytoskeletal reorganization and directional migration in human neutrophils. PLoS One 8: e73063, 2013

Sapey E, Greenwood H, Walton G, Mann E, Love A, Aaronson N, Insall RH, Stockley RA, Lord JM. Phosphoinositide 3 kinase inhibition restores neutrophil accuracy in the elderly: towards targeted treatments for immunesenescence. Blood, in press 2013

Tang H, Li A, Bi J, Veltman DM, Zech T, Spence HJ, Yu X, Timpson P, Insall RH, Frame MC, Machesky LM. Loss of Scar/WAVE complex promotes N-WASP- and FAK-dependent invasion. Curr Biol 23(2): 107-17, 2013

2012

Ura S, Pollitt AY, Veltman DM, Morrice NA, Machesky LM, Insall RH. Pseudopod growth and evolution during cell movement is controlled through SCAR/WAVE dephosphorylation. Curr Biol 22(7): 553-61, 2012

Veltman DM, King JS, Machesky LM, Insall RH. SCAR knockouts in Dictyostelium: WASP assumes SCAR's position and upstream regulators in pseudopods. J Cell Biol 198(4): 501-8, 2012

Pakes NK, Veltman DM, Rivero F, Nasir J, Insall R, Williams RS. The Rac GEF ZizB regulates development, cell motility and cytokinesis in Dictyostelium. J Cell Sci 125(Pt 10): 2457-65, 2012

Spence HJ, Timpson P, Tang HR, Insall RH, Machesky LM. Scar/WAVE3 contributes to motility and plasticity of lamellipodial dynamics but not invasion in 3D. Biochem J 448(1): 35-42, 2012

Yu X, Zech T, McDonald L, Gonzalez EG, Li A, Macpherson I, Schwarz JP, Spence H, Futó K, Timpson P, Nixon C, Ma Y, Anton IM, Visegrády B, Insall RH, Oien K, Blyth K, Norman JC, Machesky LM. N-WASP coordinates the delivery and F-actin-mediated capture of MT1-MMP at invasive pseudopods. J Cell Biol 199(3): 527-44, 2012

Images

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Lab Members

insall group

Post-docs

Shashi Singh
Olivia Susanto
Luke Tweedy (CRUK Multidisciplinary Award)

Scientific Officer

Peter Thomason

PhD Students

Clelia Amato
Yvette Koh

Former Lab Members

Laura Park, Post-doc, Paul O'Gorman Leukaemia Research Centre
Douwe Veltman, Fellow, MRC LMB, Cambridge

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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