Laura Machesky - Migration, Invasion and Metastasis

Introduction

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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

Committee membership

American Society for Cell Biology Council, 2012
Board of Directors, Company of Biologists
2010-present: CR-UK Biological Sciences Committee
2008-present: Wellcome Trust Basic Science Interview Committee
2007-present: AICR Scientific Advisory Committee

Honours and awards

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

2014

Garcia E, Machesky LM, Jones GE, Anton IM. WIP is necessary for matrix invasion by breast cancer cells. Eur J Cell Biol 2014. Epub 2014/08/30.

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

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 2014. Epub 2014/07/31.

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

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

2011

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 doi: 10.1242/ jcs.080986, published online 23 Nov 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.

Heath RJ, Leong JM, Visegrady B, Machesky LM, Xavier RJ (2011). Bacterial and Host Determinants of MAL Activation upon EPEC Infection: The Roles of Tir, ABRA, and FLRT3. PLoS Pathog. 7, e1001332.

Lindsay CR, Lawn S, Campbell AD, Faller WJ, Rambow F, Mort RL, Timpson P, Li A, Cammareri P, Ridgway RA, Morton JP, Doyle B, Hegarty S, Rafferty M, Murphy IG, McDermott EW, Sheahan K, Pedone K, Finn AJ, Groben PA, Thomas NE, Hao H, Carson C, Norman JC, Machesky LM, Gallagher WM, Jackson IJ, Van Kempen L, Beermann F, Der C, Larue L, Welch HC, Ozanne BW, Sansom OJ. P-Rex1 is required for efficient melanoblast migration and melanoma metastasis. Nat Commun doi: 10.1038/ncomms1560, published online 22 Nov 2011

Ramsay AK, McCracken SRC, Soofi M, Morland R, Fleming J, Yu AX, Machesky L, Nixon C, Edwards DE, Nuttall RK, Seywright M, Keller E, Leung HY (2011). ERK5 signalling in prostate cancer promotes an invasive phenotype. Br J Cancer 104, 664-72.

Thomas SG, Calaminus SD, Machesky LM, Alberts AS, Watson SP (2011). G-protein coupled and ITAM receptor regulation of the formin FHOD1 through Rho Kinase in platelets. J Thromb Haemost. 2011 May 23. doi: 10.1111/j.1538-7836.2011.04357.x. [Epub ahead of print].

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.

2010

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

Visegrady B, Machesky LM (2010). Myopathy-causing actin mutations promote defects in serum-response factor signalling. Biochem J. 427, 41-8.

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

Brooks SP, Coccia M, Tang HR, Kanuga N, Machesky LM, Bailly M, Cheetham ME, Hardcastle AJ (2010). The Nance-Horan syndrome protein encodes a functional WAVE homology domain (WHD) and is important for co-ordinating actin remodelling and maintaining cell morphology. Hum Mol Genet. 19, 2421-32.

Serrels B, Sandilands E, Serrels A, Baillie G, Houslay MD, Brunton VG, Canel M, Machesky LM, Anderson KI, Frame MC (2010). A complex between FAK, RACK1, and PDE4D5 controls spreading initiation and cancer cell polarity. Curr Biol. 20, 1086-92.

Stein T, Cosimo E, Yu X, Smith PR, Simon R, Cottrell L, Pringle MA, Bell AK, Lattanzio L, Sauter G, Lo Nigro C, Crook T, Machesky LM, Gusterson BA (2010). Loss of reelin expression in breast cancer is epigenetically controlled and associated with poor prognosis. Am J Pathol. 177, 2323-33.

2009

Mardakheh FK,Yekezare M, Machesky LM, Heath JK (2009). Spred2 interaction with the late endosomal protein NBR1 down-regulates fibroblast growth factor receptor signaling. J Cell Biol. 187, 265-77.

Vandamme D, Lambert E,Waterschoot D,Tondeleir D,Vandekerckhove J, Machesky LM, Constantin B, Rommelaere H,Ampe C (2009). Phenotypes induced by NM causing alpha-skeletal muscle actin mutants in fibroblasts, Sol 8 myoblasts and myotubes. BMC Res Notes 2, 40.

Insall RH, Machesky LM (2009). Actin dynamics at the leading edge: from simple machinery to complex networks. Dev Cell 17, 310-22.

Machesky LM, Tang HR (2009). Actin-based protrusions: promoters or inhibitors of cancer invasion? Cancer Cell 16, 5-7.

Lab Members

machesky lab 2013

Post-docs

Amelie Juin
Karthic Swaminathan
Benjamin Tyrrell
Iben Veland (University of Copenhagen)

Scientific Officer

Heather Spence

Clinical Research Fellow

Hayley Morris (MRC)

PhD Students

Loic Fort
Emma Woodham

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, CR-UK Paterson Institute, Manchester

Research

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Read more about the Research Groups working at the Beatson Institute.

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Seminars

Beatson Institute Seminars

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

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