Prof Laura Machesky FRSE - Migration, Invasion and Metastasis
Introduction
Normal tissues have a balance of physical forces, keeping their architecture and organisation intact. In contrast, this balance is disrupted in tumours, leading to abnormal architecture, progression and spread. These imbalances affect migration and invasion, which in turn places metabolic demands on the cells and can lead to rewiring of cellular responses. When tumour cells escape to new tissues, metastatic seeding occurs, but cells can either rapidly proliferate and grow into a new tumour or remain quiet until conditions trigger outgrowth. Our group use molecular cell biology, in vivo models and advanced imaging to understand how stresses and signalling in the tumour and the microenvironment drive metastasis and reawakening of disseminated cancer cells. Using bioengineering, we are also modelling the tumour microenvironment and the metastatic niche, so that its complexity can be better understood. We focus mainly on pancreatic cancer, which is a very aggressive cancer, known for its stiff fibrotic stroma and metastatic behaviour.
EmailSee the following CRUK Science blogs to find out more about the work of Prof Machesky's group:
- Pancreatic cancer cells use the same energy as sprinters' muscles to spread
- Seeing the effects of proteins we know nothing about
- "How do tumours 'know' where to spread?"
Other funding:
Lab Report
Key Publications
Papalazarou V, Zhang T, Paul NR, Juin A, Cantini M, Maddocks ODK, Salmeron-Sanchez M, Machesky LM. The creatine–phosphagen system is mechanoresponsive in pancreatic adenocarcinoma and fuels invasion and metastasis. Nature Metabolism. 2020;2:62-80.
Nikolaou S, Machesky LM. The stressful tumour environment drives plasticity of cell migration programmes, contributing to metastasis. The Journal of pathology;
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.
Papalazarou V, Salmeron-Sanchez M, Machesky LM. Tissue engineering the cancer microenvironment-challenges and opportunities. Biophys Rev 2018. 10: 1695-1711.
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: 1159-71.
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
2023
Wilkinson EL, Brennan LC, Harrison OJ, Crane-Smith Z, Gautier P, Keighren MA, Budd P, Swaminathan K, Machesky LM, Allinson SL, Jackson IJ, Mort RL. Genetically engineered multicistronic allele of Pmel yielding highly specific CreERT2-mediated recombination in the melanocyte lineage. Pigment Cell Melanoma Res. 2023;36:71-77.
Machesky LM. CYRI proteins: controllers of actin dynamics in the cellular 'eat vs walk' decision. Biochem Soc Trans. 2023;10.1042/bst20221354.
Machesky LM. Deadly actin collapse by disulfidptosis. Nat Cell Biol. 2023;25:375-376.
2022
Jaber-Hijazi F, Swaminathan K, Gilroy K, Wenzel AT, Lagnado A, Kirschner K, Robertson N, Reid C, Fullarton N, Pawlikowski J, Blyth K, Mesirov JP, Rai TS, Passos JF, Machesky LM, Adams PD. Inactivation of histone chaperone HIRA unmasks a link between normal embryonic development of melanoblasts and maintenance of adult melanocyte stem cells. bioRxiv; 10.1101/2022.04.22.4891662022:2022.2004.2022.489166.
Le AH, Machesky LM. Image-based Quantification of Macropinocytosis Using Dextran Uptake into Cultured Cells. Bio Protoc. 2022;12:e4367.
Nikolaou S, Juin A, Whitelaw JA, Paul NR, Fort L, Nixon C, Spence HJ, Bryson S, Machesky LM. CYRI-B mediated macropinocytosis drives metastasis via lysophosphatidic acid receptor uptake. bioRxiv. 2022;Volume:2022.2011.2023.517689.
Papalazarou V, Drew J, Juin A, Spence HJ, Whitelaw J, Nixon C, Salmeron-Sanchez M, Machesky LM. Collagen VI expression is negatively mechanosensitive in pancreatic cancer cells and supports the metastatic niche. J Cell Sci. 2022;135.
2021
Callenberg C, Lyons A, Brok DD, Fatima A, Turpin A, Zickus V, Machesky L, Whitelaw J, Faccio D, Hullin MB. Super-resolution time-resolved imaging using computational sensor fusion. Sci Rep. 2021;11:1689.
Floerchinger A, Murphy KJ, Latham SL, Warren SC, McCulloch AT, Lee YK, Stoehr J, Mélénec P, Guaman CS, Metcalf XL, Lee V, Zaratzian A, Da Silva A, Tayao M, Rolo S, Phimmachanh M, Sultani G, McDonald L, Mason SM, Ferrari N, Ooms LM, Johnsson AE, Spence HJ, Olson MF, Machesky LM, Sansom OJ, Morton JP, Mitchell CA, Samuel MS, Croucher DR, Welch HCE, Blyth K, Caldon CE, Herrmann D, Anderson KI, Timpson P, Nobis M. Optimizing metastatic-cascade-dependent Rac1 targeting in breast cancer: Guidance using optical window intravital FRET imaging. Cell Rep. 2021;36(11):109689.
Le AH, Yelland T, Paul NR, Fort L, Nikolaou S, Ismail S, Machesky LM. CYRI-A limits invasive migration through macropinosome formation and integrin uptake regulation. J Cell Biol. 2021;220.
Pickering KA, Gilroy K, Cassidy JW, Fey SK, Najumudeen AK, Zeiger LB, Vincent DF, Gay DM, Johansson J, Fordham RP, Miller B, Clark W, Hedley A, Unal EB, Kiel C, McGhee E, Machesky LM, Nixon C, Johnsson AE, Bain M, et al. A RAC-GEF network critical for early intestinal tumourigenesis. Nat Commun. 2021;12:56.
Swaminathan K, Campbell A, Papalazarou V, Jaber-Hijazi F, Nixon C, McGhee E, Strathdee D, Sansom OJ, Machesky LM. The RAC1 Target NCKAP1 Plays a Crucial Role in the Progression of Braf;Pten-Driven Melanoma in Mice. J Invest Dermatol. 2021;141(3):628-637.e615.
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(3):226-237.e224.
Drew J, Machesky LM. The liver metastatic niche: modelling the extracellular matrix in metastasis. Dis Model Mech. 2021;14:dmm048801
Machesky LM, Insall RH. WAVE complex regulation by force. Nat Cell Biol. 2021; 23:1111–1112
Olson MF, Machesky LM. MICAL2 fine-tunes Arp2/3 for actin branching. J Cell Biol. 2021; 220:e202106176
Papalazarou V, Machesky LM. The cell pushes back: The Arp2/3 complex is a key orchestrator of cellular responses to environmental forces. Curr Opin Cell Biol. 2021; 68: ed2021:37-44.
2020
Lucendo-Villarin B, Meseguer-Ripolles J, Drew J, Fischer L, Ma WSE, Flint O, Simpson K, Machesky L, Mountford J, Hay D. Development of a cost effective automated platform to produce human liver spheroids for basic and applied research. Biofabrication. 2020; 13: 015009
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(10):33.
Nikolaou S, Machesky LM. The stressful tumour environment drives plasticity of cell migration programmes, contributing to metastasis. The Journal of pathology; 2020; 250: 612-62
Papalazarou V, Swaminathan K, Jaber-Hijazi F, Spence H, Lahmann I, Nixon C, Salmeron-Sanchez M, Arnold HH, Rottner K, Machesky LM. The Arp2/3 complex is critical for colonisation of the mouse skin by melanoblasts. Development. 2020; 147: dev194555
Papalazarou V, Machesky LM. The cell pushes back: The Arp2/3 complex is a key orchestrator of cellular responses to environmental forces. Current Opinion in Cell Biology. 2021;68:37-44.
Papalazarou V, Zhang T, Paul NR, Juin A, Cantini M, Maddocks ODK, Salmeron-Sanchez M, Machesky LM. The creatine–phosphagen system is mechanoresponsive in pancreatic adenocarcinoma and fuels invasion and metastasis. Nature Metabolism. 2020;2:62-80.
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(8):e3000774.
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(6507):eaay9792.
Whitelaw JA, Swaminathan K, Kage F, Machesky LM. The WAVE Regulatory Complex Is Required to Balance Protrusion and Adhesion in Migration. Cells. 2020;9(7): 1635
Zickus V, Wu ML, Morimoto K, Kapitany V, Fatima A, Turpin A, Insall R, Whitelaw J, Machesky L, Bruschini C, Faccio D, Charbon E. Fluorescence lifetime imaging with a megapixel SPAD camera and neural network lifetime estimation. Sci Rep. 2020;10(1):20986.
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.e4.
Bachg AC, Horsthemke M, Skryabin BV, Klasen T, Nagelmann N, Faber C, Woodham E, Machesky LM, Bachg S, Stange R, Jeong HW, Adams RH, Bahler M, Hanley PJ. Phenotypic analysis of Myo10 knockout (Myo10(tm2/tm2)) mice lacking full-length (motorized) but not brain-specific headless myosin X. Scientific reports 2019; 9: 597.
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.
Kugeratski FG, Atkinson SJ, Neilson LJ, Lilla S, Knight JRP, Serneels J, Juin A, Ismail S, Bryant DM, Markert EK, Machesky LM, Mazzone M, Sansom OJ, Zanivan S. Hypoxic cancer-associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling. Science signaling 2019; 12. pii: eaan8247.
Machesky LM. Rab11FIP proteins link endocytic recycling vesicles for cytoskeletal transport and tethering. Biosci Rep. 2019; 39. pii: BSR20182219
Nikolaou S, Machesky LM. Invasion by Force: The C. elegans Anchor Cell Leads the Way. Developmental cell. 2019;48:287-288.
Schurr Y, Sperr A, Volz J, Beck S, Reil L, Kusch C, Eiring P, Bryson S, Sauer M, Nieswandt B, Machesky L, Bender M. Platelet lamellipodia formation is not required for thrombus formation and stability. Blood. 2019;10.1182/blood.2019002105.
Whitelaw JA, Lilla S, Paul NR, Fort L, Zanivan S, Machesky LM. CYRI/ Fam49 Proteins Represent a New Class of Rac1 Interactors. Communicative & integrative biology. 2019;12:112-118.
2018
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: 1159-71.
Laurent-Gengoux P, Petit V, Aktary Z, Gallagher S, Tweedy L, Machesky L, Larue L. Simulation of melanoblast displacements reveals new features of developmental migration. Development 2018; 145 pii: dev160200.
Morris HT, Fort L, Spence HJ, Patel R, Vincent DF, Park JH, Snapper SB, Carey FA, Sansom OJ, Machesky LM. Loss of N-WASP drives early progression in an Apc model of intestinal tumourigenesis. J Pathol 2018; 245: 337-48
Papalazarou V, Salmeron-Sanchez M, Machesky LM. Tissue engineering the cancer microenvironment-challenges and opportunities. Biophys Rev 2018.
2017
Giampazolias E, Zunino B, Dhayade S, Bock F, Cloix C, Cao K, Roca A, Lopez J, Ichim G, Proics E, Rubio-Patino C, Fort L, Yatim N, Woodham E, Orozco S, Taraborrelli L, Peltzer N, Lecis D, Machesky L, Walczak H et al. Mitochondrial permeabilization engages NF-kappaB-dependent anti-tumour activity under caspase deficiency. Nat Cell Biol 2017; 19: 1116-29
Machesky L, Braga VMM. So far, yet so close: alpha-Catenin dimers help migrating cells get together. J Cell Biol 2017; 216: 3437-9
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, Roman-Fernandez A, ElMaghloob Y, Hernandez-Fernaud JR, Adams RH, Ismail S, Bryant DM et al. Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium. EMBO J 2017; 36: 2373-89
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 2017; 28: 372-9
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
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. 2016; 6: 23590
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 2016; 128: 371-83
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 2016; 25: 1-8
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. 2016; 29: 559-71
Lab Members
Associate Scientist
Amelie Juin
Principal Scientific Officer
Heather Spence
PhD Students
Hakem Albilasi (Saudi Government Scholarship)
Elaine Ma (ESPRC Physics of Life, Centre for Doctoral Training Bioengineering)
Juda Milvidaite (ESPRC Physics of Life, Centre for Doctoral Training Bioengineering)
Sonia Rolo
Former Lab Members
Simon Calaminus, Lecturer, Hull University
Loic Fort
Ang Li, Post-doc, New York, USA
Hannah Schachtner, Post-doc, Berlin, Germany
Hao Ran Tang, Post-doc, CRUK Manchester Institute
