Robert Insall - Cell Migration and Chemotaxis

Introduction

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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

2016

Tweedy L, Knecht DA, Mackay GM, Insall RH. Self-Generated Chemoattractant Gradients: Attractant Depletion Extends the Range and Robustness of Chemotaxis. PLoS Biol. 2016 Mar 16;14(3):e1002404

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

2011

Carnell M, Zech T, Calaminus SD, Ura S, Hagedorn M, Johnston SA, May RC, Soldati T, Machesky LM, Insall RH (2011). Actin polymerization driven by WASH causes V-ATPase retrieval and vesicle neutralization before exocytosis. J Cell Biol. 193, 831-9.

King JS, Veltman DM, Insall RH. The induction of autophagy by mechanical stress. Autophagy 2011; 7: 1490-9

Neilson MP, Mackenzie JA, Webb SD, Insall RH. Modeling Cell Movement and Chemotaxis Using Pseudopod-Based Feedback. SIAM J Sci Comput 2011; 33, 1035-57

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

Veltman DM, Auciello G, Spence HJ, Machesky LM, Rappoport JZ, Insall RH (2011). Functional analysis of Dictyostelium IBARa reveals a conserved role of the I-BAR domain in endocytosis. Biochem J. 436, 45-52.

Itakura A, Verbout NG, Phillips KG, Insall RH, Gailani D, Tucker EI, Gruber A, McCarty OJ (2011). Activated factor XI inhibits chemotaxis of polymorphonuclear leukocytes. J Leukoc Biol. 90(5):923-7, 2011

Sapey E, Stockley JA, Greenwood H, Ahmad A, Bayley D, Lord JM, Insall RH, Stockley RA (2011). Behavioral and structural differences in migrating peripheral neutrophils from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 183, 1176-86.

Li A, Ma Y, Yu X, Mort RL, Lindsay CR, Stevenson D, Strathdee D, Insall RH, Chernoff J, Snapper SB, Jackson IJ, Larue L, Sansom OJ, Machesky LM. Rac1 Drives Melanoblast Organization during Mouse Development by Orchestrating Pseudopod- Driven Motility and Cell-Cycle Progression. Dev Cell 2011; 21: 722-34

Zech T, Calaminus SDJ, Caswell PT, Spence HJ, Carnell MJ, Insall RH, Norman JC, Machesky LM. The Arp2/3 activator WASH regulates alpha-5 beta-1 integrin mediated invasive migration. J Cell Sci 124(Pt 22):3753-9, 2011

Carnell MH, Insall RH. Actin on disease - understanding the pathobiology of cell motility with Dictyostelium discoideum. Sem Cell Dev Biol. 22, 82, 2011

Davidson AJ, Insall RH (2011). Actin-based motility: WAVE regulatory complex structure reopens old SCARs. Curr Biol. 21, R66-8.

Insall RH (2011). Dogma bites back--the evidence for branched actin. Trends Cell Biol. 21, 2; author reply 4-5.

2010

King JS, Veltman DM, Georgiou M, Baum B, Insall RH (2010). SCAR/WAVE is activated at mitosis and drives myosin-independent cytokinesis. J Cell Sci. 123, 2246-55.

Muinonen-Martin AJ, Veltman DM, Kalna G, Insall RH (2010). An Improved Chamber for Direct Visualisation of Chemotaxis. PLoS ONE 5, e15309.

Neilson MP, Mackenzie JA, Webb SD, Insall RH (2010). Use of the parameterised finite element method to robustly and efficiently evolve the edge of a moving cell. Integrative Biol. 2, 687-95.

Veltman DM, Insall RH (2010). WASP family proteins - their evolution and its physiological implications. Mol Biol Cell 21, 2880-93.

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

Images

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Lab Members

insall lab 2013

Post-docs

Jan Ohotski
Olivia Susanto
Luke Tweedy

Scientific Officer

Peter Thomason

PhD Students

Clelia Amato
José Batista (FCT, Portuguese Government)
Yvette Koh

Visitor

Sebald Verkuijl

Former Lab Members

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

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