Prof Robert Insall FRSE - Cell Migration and Chemotaxis
Introduction
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.
Another is the regulation of actin polymerisation. Actin is the most abundant protein in eukaryotic cells. It polymerises 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 polymerise 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.
EmailOther funding:
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
MRC MCMB board
RCUK Technologies Touching Life (TTL) panel
Faculty of 1000
Honours and awards
Fellow of the Royal Society of Edinburgh, 2014
Recent Publications
2022
Buracco S, Singh S, Claydon S, Paschke P, Tweedy L, Whitelaw J, McGarry L, Thomason PA, Insall RH. The Scar/WAVE complex drives normal actin protrusions without the Arp2/3 complex, but proline-rich domains are required. bioRxiv. 2022;Volume:2022.2005.2014.491902.
Dowdell A, Paschke P, Thomason P, Tweedy L, Insall RH. Competition between chemoattractants causes unexpected complexity and can explain negative chemotaxis. bioRxiv. 2022;10.1101/2022.12.07.519354:2022.2012.2007.519354.
Insall RH, Paschke P, Tweedy L. Steering yourself by the bootstraps: how cells create their own gradients for chemotaxis. Trends Cell Biol. 2022; 585-596
Singh SP, Insall RH. Under-Agarose Chemotaxis and Migration Assays for Dictyostelium. Methods Mol Biol. 2022;2438:467-482.
Singh SP, Paschke P, Tweedy L, Insall RH. AKT and SGK kinases regulate cell migration by altering Scar/WAVE complex activation and Arp2/3 complex recruitment. Front Mol Biosci. 2022;9:965921.
2021
Singh SP, Thomason P, Insall R. Extracellular signalling modulates Scar/WAVE complex activity through Abi phosphorylation. bioRxiv. 2021;10.1101/2021.10.09.462405:2021.2010.2009.462405.
Yang Y, Li D, Chao X, Singh SP, Thomason P, Yan Y, Dong M, Li L, Insall RH, Cai H. Leep1 interacts with PIP3 and the Scar/WAVE complex to regulate cell migration and macropinocytosis. J Cell Biol. 2021;220:e202010096
Yelland T, Le AH, Nikolaou S, Insall R, Machesky L, Ismail S. Structural Basis of CYRI-B Direct Competition with Scar/WAVE Complex for Rac1. Structure. 2021;29:226-237.e224.
Insall R. Actin in 2021. Curr Biol. 2021;31:R496-r498.
Machesky LM, Insall RH. WAVE complex regulation by force. Nat Cell Biol. 2021; 23:1111–1112
2020
McMenamin PG, Shields GT, Seyed-Razavi Y, Kalirai H, Insall RH, Machesky LM, Coupland SE. Melanoblasts Populate the Mouse Choroid Earlier in Development Than Previously Described. Invest Ophthalmol Vis Sci. 2020;61:33.
Singh SP, Thomason PA, Lilla S, Schaks M, Tang Q, Goode BL, Machesky LM, Rottner K, Insall RH. Cell-substrate adhesion drives Scar/WAVE activation and phosphorylation by a Ste20-family kinase, which controls pseudopod lifetime. PLoS Biol. 2020;18:e3000774.
Tweedy L, Insall RH. Self-Generated Gradients Yield Exceptionally Robust Steering Cues. Frontiers in cell and developmental biology. 2020;8:133.
Tweedy L, Thomason PA, Paschke PI, Martin K, Machesky LM, Zagnoni M, Insall RH. Seeing around corners: Cells solve mazes and respond at a distance using attractant breakdown. Science. 2020;369:eaay9792.
2019
Amato C, Thomason PA, Davidson AJ, Swaminathan K, Ismail S, Machesky LM, Insall RH. WASP Restricts Active Rac to Maintain Cells' Front-Rear Polarization. Current biology : CB. 2019;29:4169-4182
Buckley CM, Heath VL, Gueho A, Bosmani C, Knobloch P, Sikakana P, Personnic N, Dove SK, Michell RH, Meier R, Hilbi H, Soldati T, Insall RH, King JS. PIKfyve/Fab1 is required for efficient V-ATPase and hydrolase delivery to phagosomes, phagosomal killing, and restriction of Legionella infection. PLoS pathogens 2019; 15: e1007551.
Juin A, Spence HJ, Martin KJ, McGhee E, Neilson M, Cutiongco MFA, Gadegaard N, Mackay G, Fort L, Lilla S, Kalna G, Thomason P, Koh YWH, Norman JC, Insall RH, Machesky LM. N-WASP Control of LPAR1 Trafficking Establishes Response to Self-Generated LPA Gradients to Promote Pancreatic Cancer Cell Metastasis. Developmental cell. 2019;51:431-445
Kadir SR, Insall RH, Moffatt G, McGhee J, Livingstone D. Analogies in 3D molecular visualisations: development of a cell biology animation 'How cells move - a new interpretation of old data'. Journal of visual communication in medicine. 2019;43:35-46
Mackenzie JA, Nolan M, Rowlatt CF, Insall RH. An Adaptive Moving Mesh Method for Forced Curve Shortening Flow. SIAM journal on scientific computing : a publication of the Society for Industrial and Applied Mathematics. 2019;41:A1170-a1200.
Paschke P, Knecht DA, Williams TD, Thomason PA, Insall RH, Chubb JR, Kay RR, Veltman DM. Genetic Engineering of Dictyostelium discoideum Cells Based on Selection and Growth on Bacteria. Journal of visualized experiments: JoVE 2019; (143).
Tweedy L, Witzel P, Heinrich D, Insall RH, Endres RG. Screening by changes in stereotypical behavior during cell motility. Scientific reports. 2019;9:8784
2018
Davidson AJ, Amato C, Thomason PA, Insall RH. WASP family proteins and formins compete in pseudopod- and bleb-based migration. J Cell Biol 2018; 217: 701-14.
Fort L, Batista JM, Thomason PA, Spence HJ, Whitelaw JA, Tweedy L, Greaves J, Martin KJ, Anderson KI, Brown P, Lilla S, Neilson MP, Tafelmeyer P, Zanivan S, Ismail S, Bryant DM, Tomkinson NCO, Chamberlain LH, Mastick GS, Insall RH, Machesky LM. Fam49/CYRI interacts with Rac1 and locally suppresses protrusions. Nat Cell Biol. 2018 Oct; 20(10): 1159-71.
Heinrich D, Barnett R, Tweedy L, Insall R, Stallforth P, Winckler T. The Chemoattractant Glorin Is Inactivated by Ester Cleavage during Early Multicellular Development of Polysphondylium pallidum. ACS Chem Biol 2018; 13: 1506-13.
Pan M, Neilson MP, Grunfeld AM, Cruz P, Wen X, Insall RH, Jin T. A G-protein-coupled chemoattractant receptor recognizes lipopolysaccharide for bacterial phagocytosis. PLoS Biol 2018; 16: e2005754.
Paschke P, Knecht DA, Silale A, Traynor D, Williams TD, Thomason PA, Insall RH, Chubb JR, Kay RR, Veltman DM. Rapid and efficient genetic engineering of both wild type and axenic strains of Dictyostelium discoideum. PLoS One 2018; 13: e0196809.
Schaks M, Singh SP, Kage F, Thomason P, Klunemann T, Steffen A, Blankenfeldt W, Stradal TE, Insall RH, Rottner K. Distinct Interaction Sites of Rac GTPase with WAVE Regulatory Complex Have Non-redundant Functions in Vivo. Curr Biol 2018;28:3674-3684
Song L, Rijal R, Karow M, Stumpf M, Hahn O, Park L, Insall R, Schroder R, Hofmann A, Clemen CS, Eichinger L. Expression of N471D strumpellin leads to defects in the endolysosomal system. Dis Model Mech 2018;11: dmm.033449.
Visweshwaran SP, Thomason PA, Guerois R, Vacher S, Denisov EV, Tashireva LA, Lomakina ME, Lazennec-Schurdevin C, Lakisic G, Lilla S, Molinie N, Henriot V, Mechulam Y, Alexandrova AY, Cherdyntseva NV, Bieche I, Schmitt E, Insall RH, Gautreau A. The trimeric coiled-coil HSBP1 protein promotes WASH complex assembly at centrosomes. EMBO J 2018; 37(13): embj.201797706.
2017
Ferguson EA, Matthiopoulos J, Insall RH, Husmeier D. Statistical inference of the mechanisms driving collective cell movement. Journal of the Royal Statistical Society: Series C (Applied Statistics) 2017; 66: 869-90
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; 6: pii: e24119.
Susanto O, Koh YWH, Morrice N, Tumanov S, Thomason PA, Nielson M, Tweedy L, Muinonen-Martin AJ, Kamphorst JJ, Mackay GM, Insall RH. LPP3 mediates self-generation of chemotactic LPA gradients by melanoma cells. J Cell Sci 2017; 130: 3455-66
Thomason PA, King JS, Insall RH. Mroh1, a lysosomal regulator localised by WASH-generated actin. J Cell Sci 2017; 130: 1785-95
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 2017; 27: 624-37
Susanto O, Insall RH. LPP3, LPA and self-generated chemotactic gradients in biomedical science. Comm Integ Biol 2017: e1398870.
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
Lab Members
Post-docs
Simona Buracco
Hannah Donnelly
Abhimanyu Kiran
Data Scientist
Durga Akhil Yeduresi
PhD Students
Sophie G. Claydon
Lucas Farndale
Elena Mandrou
Joshua Roche
Christopher Walsh
Former Lab Members
Clelia Amato
Yvette Koh
Laura Park, Post-doc, Paul O'Gorman Leukaemia Research Centre
Olivia Susanto
Douwe Veltman, Fellow, MRC LMB, Cambridge
