Laura Machesky - Migration, Invasion and Metastasis

Introduction

MacheskyL

Mobilisation of the actin cytoskeleton is important for cell migration, shape change, and interactions with other cells and the environment. Additionally, alterations in cytoskeletal signalling pathways are increasingly being recognised as important for cancer invasion and metastasis.

We aim to understand the control and mechanisms of actin assembly in various normal and cancer cells with the hope to understand fundamental aspects of cell movement.

These studies impact on our understanding of normal development, immune system function, haemostasis and cancer.

 

In collaboration with Martin Drysdale (Beatson Drug Discovery) and Jennifer Morton, our group has a project funded by the Pancreatic Cancer Research Fund entitled "Development of new therapies against metastasis of pancreatic cancer".

Lab Report

Key Publications

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 21: 722- 34, 2011

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

Li A, Dawson JC, Forero-Vargas M, Spence HJ, Yu X, Konig I, Anderson K, Machesky LM. The actin-bundling protein fascin stabilizes actin in invadopodia and potentiates protrusive invasion. Curr Biol 20: 339-45, 2010

May RC, Caron E, Hall A, Machesky LM. Involvement of the Arp2/3 complex in FcgR and CR3 mediated phagocytosis. Nature Cell Biol 2: 246-8, 2000

Machesky LM, Mullins RD, Higgs HN, Kaiser DA, Blanchoin L, May RC, Hall ME, Pollard TD. Wasp-related protein Scar activates dendritic nucleation of actin filaments by Arp2/3 complex. Proc Natl Acad Sci USA 96: 3739-44, 1999

Machesky LM, Insall RH. Scar and the related Wiskott-Aldrich syndrome protein, WASP, regulate the actin cytoskeleton through the Arp2/3 complex. Curr Biol 8: 1347-56, 1998

Biography

Education and qualifications

1993: PhD, The Johns Hopkins School of Medicine, Supervisor Thomas D. Pollard
1987: BSc, Chemistry and Biology (GPA 3.98/4.00), Alma College, USA

Appointments

2007-present: Professor of Cell Biology, CRUK Beatson Institute
2007-2010: MRC Senior Research Fellow, CRUK Beatson Institute
1999-2007: MRC Career Development Fellow, MRC Senior Research Fellow & Professor of Cell Biology, School of Biosciences University of Birmingham
1997-1998: MRC Career Development Fellow with Alan Hall, MRC-LMCB, London
1995-1997: Damon Runyon Walter Winchell Cancer Research Posdoctoral Fellow with Alan Hall, MRC-LMCB, London
1993-1995: Damon Runyon Walter Winchell Cancer Research Postdoctoral Fellow with Rob Kay, MRC-LMB, Cambridge

Current committee membership

American Society for Cell Biology Council, 2012
Board of Directors, Company of Biologists
Science Advisory Board, UCL Institute for the Physics of Living Systems
Wellcome Trust/Royal Society Fellowships Interview Panel

Honours and awards

Fellow of the Academy of Medical Sciences, 2016
Fellow of the Royal Society of Edinburgh, 2014
Elected a Member of the European Molecular Biology Organization, 2012
Keith R. Porter Fellowship, 2011
American Society for Cell Biology, Women in Cell Biology Junior Award, 2001

Recent Publications

2017

Reid SE, Kay EJ, Neilson LJ, Henze AT, Serneels J, McGhee EJ, Dhayade S, Nixon C, Mackey JB, Santi A, Swaminathan K, Athineos D, Papalazarou V, Patella F, Román-Fernández Á, ElMaghloob Y, Hernandez-Fernaud JR, Adams RH, Ismail S, Bryant DM, Salmeron-Sanchez M, Machesky LM, Carlin LM, Blyth K, Mazzone M, Zanivan S.Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium. EMBO J. 2017 Jul 10. pii: e201694912. doi: 10.15252/embj.201694912. [Epub ahead of print]

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

Garcia E, Ragazzini C, Yu XZ, Cuesta-Garcia E, de la Serna JB, Zech T, Sarrio D, Machesky LM, Anton IM. WIP and WICH/WIRE co-ordinately control invadopodium formation and maturation in human breast cancer cell invasion. Sci Rep 6: 23590, 2016

Sinclair A, Park L, Shah M, Drotar M, Calaminus S, Hopcroft LEM, Kinstrie R, Guitart AV, Dunn K, Abraham SA, Sansom O, Michie AM, Machesky L, Kranc KR, Graham GJ, Pellicano F, Holyoake TL. CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells. Blood 128: 371-83, 2016

Thomas SG, Poulter NS, Bem D, Finney B, Machesky LM, Watson SP. The actin binding proteins cortactin and HS1 are dispensable for platelet actin nodule and megakaryocyte podosome formation. Platelets 25: 1-8, 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

2015

Lindsay CR, Li A, Faller W, Ozanne B, Welch H, Machesky LM, Sansom OJ. A Rac1-Independent Role for P-Rex1 in Melanoblasts. J Invest Dermatol 135: 314-8, 2015

Ma Y, Faller WJ, Sansom OJ, Brown ER, Doig TN, Melton DW, Machesky LM. Fascin expression is increased in metastatic lesions but does not correlate with progression nor outcome in melanoma. Melanoma Res 25: 169-72, 2015

Rainero E, Howe JD, Caswell PT, Jamieson NB, Anderson K, Critchley DR, Machesky L, Norman JC. Ligand-Occupied Integrin Internalization Links Nutrient Signaling to Invasive Migration. Cell Rep 2015. doi: 10.1016/j.celrep.2014.12.037. Epub 2015 Jan 15

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

Vijayakumar V, Monypenny J, Chen XJ, Machesky LM, Lilla S, Thrasher AJ, Anton IM, Calle Y, Jones GE. Tyrosine phosphorylation of WIP releases bound WASP and impairs podosome assembly in macrophages. J Cell Sci 128: 251-65, 2015

Ma Y, Machesky LM. Fascin1 in carcinomas: Its regulation and prognostic value. Int J Cancer 137: 2534-44, 2015

Morris HT, Machesky LM. Actin cytoskeletal control during epithelial to mesenchymal transition: focus on the pancreas and intestinal tract. Br J Cancer 112: 613-20, 2015

2014

Garcia E, Machesky LM, Jones GE, Anton IM. WIP is necessary for matrix invasion by breast cancer cells. Eur J Cell Biol 93: 413-23, 2014

Li A, Morton JP, Ma Y, Karim SA, Zhou Y, Faller WJ, Woodham EF, Morris HT, Stevenson RP, Juin A, Jamieson NB, MacKay CJ, Carter CR, Leung HY, Yamashiro S, Blyth K, Sansom OJ, Machesky LM. Fascin is regulated by slug, promotes progression of pancreatic cancer in mice, and is associated with patient outcomes. Gastroenterology 146: 1386-96 e1-17, 2014

Ma Y, Machesky LM. Fascin1 in carcinomas: Its regulation and prognostic value. Int J Cancer 2014. Epub 2014/10/11.

Machesky L, Sedwick C. Laura Machesky: actin opens the way. J Cell Biol 206: 816-7, 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

Woodham EF, Machesky LM. Polarised cell migration: intrinsic and extrinsic drivers. Curr Opin Cell Biol 30C: 25-32, 2014

2013

Li A, Machesky LM. Rac1 cycling fast in melanoma with P29S. Pigment Cell Melanoma Res, in press 2013

Ma Y, Li A, Faller WJ, Libertini S, Fiorito F, Gillespie DA, Sansom OJ, Yamashiro S, Machesky LM. Fascin 1 is transiently expressed in mouse melanoblasts during development and promotes migration and proliferation. Development 140: 2203-11, 2013

Ma Y, Reynolds LE, Li A, Stevenson RP, Hodivala-Dilke KM, Yamashiro S, Machesky LM. Fascin 1 is dispensable for developmental and tumour angiogenesis. Biol Open 2: 1187-91, 2013

Schachtner H, Calaminus SD, Sinclair A, Monypenny J, Blundell MP, Leon C, Holyoake TL, Thrasher AJ, Michie AM, Vukovic M, Gachet C, Jones GE, Thomas SG, Watson SP, Machesky LM. Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane. Blood 121: 2542-52, 2013

Schachtner H, Calaminus SD, Thomas SG, Machesky LM. Podosomes in adhesion, migration, mechanosensing and matrix remodeling. Cytoskeleton (Hoboken) 70: 572-89, 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

Ampe C, Machesky LM, Nyitrai M. Biophysical approaches for investigation of the cytoskeleton. A special issue stemming from research presented at the 2012 ECF meeting: A FEBS/EMBO workshop lecture course in Pecs, Hungary. Cytoskeleton (Hoboken) 70: 539, 2013

Futo K, Bodis E, Machesky LM, Nyitrai M, Visegrady B. Membrane binding properties of IRSp53-missing in metastasis domain (IMD) protein. Biochim Biophys Acta 1831: 1651-5, 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

Sonego M, Gajendra S, Parsons M, Ma Y, Hobbs C, Zentar MP, Williams G, Machesky LM, Doherty P, Lalli G. Fascin regulates the migration of subventricular zone-derived neuroblasts in the postnatal brain. J Neurosci 33: 12171-85, 2013

Zanivan S, Meves A, Behrendt K, Schoof EM, Neilson LJ, Cox J, Tang HR, Kalna G, van Ree JH, van Deursen JM, Trempus CS, Machesky LM, Linding R, Wickstrom SA, Fassler R, Mann M. In vivo SILAC-based proteomics reveals phosphoproteome changes during mouse skin carcinogenesis. Cell Rep 3: 552-66, 2013

2012

Calaminus SDJ, Guitart A, Sinclair A, Schachtner H, Watson SP, Holyoake TL, Kranc KR, Machesky LM. Lineage tracing of PF4-Cre marks hematopoietic stem cells and their progeny. PLoS One 7(12): e51361, 2012

Dawson JC, Bruche S, Spence HJ, Braga VM, Machesky LM. Mtss1 promotes cell-cell junction assembly and stability through the small GTPase Rac1. PLoS One 7: e31141, 2012

Dawson JC, Timpson P, Kalna G., Machesky L.M. Mtss1 regulates epidermal growth factor signalling in head and neck squamous carcinoma cells. Oncogene 31(14): 1781-93, 2012

Li A, Ma Y, Jin M, Mason S, Mort RL, Blyth K, Larue L, Sansom OJ, Machesky LM. Activated Mutant NRas(Q61K) Drives Aberrant Melanocyte Signaling, Survival, and Invasiveness via a Rac1-Dependent Mechanism. J Invest Dermatol 132(11): 2610-21, 2012

Schachtner H, Li A, Stevenson D, Calaminus SD, Thomas SG, Watson SP, Sixt M, Wedlich-Soldner R, Strathdee D, Machesky LM. Tissue inducible Lifeact expression allows visualization of actin dynamics in vivo and ex vivo. Eur J Cell Biol 91(11-12): 923-9, 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, Garcia Gonzalez E, Li A, Macpherson I, Schwarz JP, Spence H, Futo K, Timpson P, Nixon C, Ma Y, Anton IM, Visegrady 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

Yu X, Machesky LM. Cells assemble invadopodia-like structures and invade into matrigel in a matrix metalloprotease dependent manner in the circular invasion assay. PLoS One 7: e30605, 2012

Li A, Machesky LM. Melanoblasts on the move: Rac1 sets the pace. Small GTPases 3: 115-9, 2012

Machesky LM, Sansom OJ. Rac1 in the driver’s seat for melanoma. Pigment Cell Melanoma Res 25: 762-4, 2012

Stevenson RP, Veltman D, Machesky LM. Actin-bundling proteins in cancer progression at a glance. J Cell Sci 125: 1073-9, 2012

Zech T, Calaminus SD, Machesky LM. Actin on trafficking: Could actin guide directed receptor transport? Cell Adh Migr 6: 476-81, 2012

Garcia E, Jones GE, Machesky LM, Anton IM. WIP: WASP-interacting proteins at invadopodia and podosomes. Eur J Cell Biol 91: 869-77, 2012

Maritzen T, Zech T, Schmidt MR, Krause E, Machesky LM, Haucke V. Gadkin negatively regulates cell spreading and motility via sequestration of the actin-nucleating ARP2/3 complex. Proc Natl Acad Sci U S A 109: 10382-7, 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: 553-61, 2012

Veltmann 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

Zanivan S, Meves A, Beherendt K, Schoof EM, Neilson LJ, Cox J, Tang HR, Kalna G, van Ree JH, Van Deursen JM, Trempus CS, Machesky LM, Linding R, Wickstrom SA, Fassler R, Mann M. In vivo SILAC-based proteomics reveals phosphoproteome changes during mouse skin carcinogenesis. Cell Rep 3(2): 552-66, 2012

Lab Members

machesky group

Post-docs

Amelie Juin
Kirsty Martin
Nikki Paul (Pancreatic Cancer Research Fund)
Karthic Swaminathan
Jamie Whitelaw

Scientific Officer

Heather Spence

PhD Students

Loic Fort
Anh Hoang Le
Vasileios Papalazarou (CRUK Glasgow Centre, joint with Manuel Salmeron-Sanchez, Glasgow)

Former Lab Members

Simon Calaminus, Lecturer, Hull University
Ang Li, Post-doc, New York, USA
Hannah Schachtner, Post-doc, Berlin, Germany
Hao Ran Tang, Post-doc, CRUK Manchester Institute

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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