Prof Jim Norman - Integrin Cell Biology
Introduction
Integrins are cell adhesion receptors involved in mediating the invasive migration, growth and metastasis of cancer cells. Data from our lab and our collaborators has established that Rab-regulated integrin trafficking contributes to cancer cell migration.
Indeed, we have now obtained detailed descriptions of the molecular machinery of integrin transport and determined how this contributes to invasive migration of cancer cells through three-dimensional matrices.
Furthermore, we have identified components of the cell's machinery for processing and transporting mRNA that make key contributions to cancer cell invasion. We are currently evaluating the molecular components of these novel pathways as potential targets for anti-cancer therapy and patient screening strategies.
Email
Lab Report
Research Highlights
- First description of the role of Rab GTPases and cell signalling pathways that control integrin recycling – key to this work was the development of assays to measure integrin trafficking which have subsequently been widely used by others in the field (Curr Biol 11:1).
- The first proteomic investigations of an endosomally-located receptor reveals PKD1 to be a partner for an integrin that regulates intracellular trafficking by phosphorylating a Rab effector (EMBO J 23:2531; J Cell Biol 177:515; Dev Cell 23:560).
- The development of novel photoactivation approaches to study integrin trafficking in living cells (Dev Cell 13:496).
- The first descriptions of the contributions made by integrin trafficking to tumour cell invasion and cell migration in 3D contexts. Key to this work was the discovery of mutant p53’s gain of function to drive invasion via Rab-coupling protein recycling (J Cell Biol 183:143; Cell 139:1327)
- Discovery of a new pathway active in cancer cells that opposes degradation of lysosomally-targetted integrins and allows their return to the plasma membrane. CLIC3, the regulator of this pathway, provides the first clear link between adhesion receptor trafficking and the progression of cancer in humans (Dev Cell 17:131)
Key Recent Publications
Christoforides C, Rainero E, Brown KK, Norman JC* and Toker A*. PKD Controls αvβ3 Integrin Recycling and Tumor Cell Invasive Migration Through its Substrate Rabaptin-5. Dev Cell. 2012; 23:560-572 *joint corresponding authors
Muller PA, Trinidad AG, Timpson P, Morton JP, Zanivan S, van den Berghe PV, Nixon C, Karim SA, Caswell PT, Noll JE, Coffill CR, Lane DP, Sansom OJ, Neilsen PM, Norman JC*, Vousden KH*. Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion. Oncogene. 2013 32: 1252-65 *joint corresponding authors
Dozynkiewicz MA, Jamieson NB, Macpherson I, Grindlay J, van den Berghe PV, von Thun A, Morton JP, Gourley C, Timpson P, Nixon C, McKay CJ, Carter R, Strachan D, Anderson K, Sansom OJ, Caswell PT, Norman JC. Rab25 and CLIC3 Collaborate to Promote Integrin Recycling from Late Endosomes/Lysosomes and Drive Cancer Progression. Dev Cell. 2012; 17: 131-45
Rainero E, Caswell PT, Muller PA, Grindlay J, McCaffrey MW, Zhang Q, Wakelam MJ, Vousden KH, Graziani A, Norman JC. Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration. J Cell Biology. 2012; 196: 277-295
von Thun A, Birtwistle M, Kalna G, Grindlay J, Strachan D, Kolch W and von Kriegsheim A, Norman JC. ERK2 drives tumour cell migration in 3D microenvironments by suppressing expression of Rab17 and Liprin-β2. J Cell Science. 2012; 125: 1465-77
Biography
Education and qualifications
1992: PhD, University of London
1985: BSc, Biochemistry, University of Southampton
Appointments
2009-present: Senior Group Leader, CRUK Scotland Institute
2005-2009: Junior Group Leader, CRUK Beatson Institute
2000-2005: Lecturer, Dept. Biochemistry, University of Leicester
1999-2004: Wellcome Career Development Fellow, Dept. Biochemistry, University of Leicester
1996-1998: Postdoctoral Fellow, Dept. Biochemistry, University of Leicester
1994-1996: Postdoctoral Fellow, Physiological Laboratory, University of Cambridge
1992-1994: Postdoctoral Fellow, Dept. Physiology, University College London
Honours and awards
Wellcome Trust Career Development Award, 1999-2004
Recent Publications
2024
Derby SJ, Dutton L, Strathdee KE, Stevenson K, Koessinger A, Jackson M, Tian Y, Yu W, McLay K, Misquitta J, Alsharif S, Clarke CJ, Gilmour L, Thomason P, McGhee E, McGarrity-Cottrell CL, Vanderlinden A, Collis SJ, Rominyi O, Lemgruber L, Solecki G, Olson M, Winkler F, Carlin LM, Heiland DH, Inman GJ, Chalmers AJ, Norman JC, Carruthers R, Birch JL. Inhibition of ATR opposes glioblastoma invasion through disruption of cytoskeletal networks and integrin internalization via macropinocytosis. Neuro Oncol. 2024;26(4):625-639.
Fercoq F, Cairns GS, Donatis MD, Mackey JBG, Floerchinger A, McFarlane A, Raffo-Iraolagoitia XL, Whyte D, Arnott LWG, Nixon C, Wiesheu R, Kilbey A, Brown L, Al-Khalidi S, Norman JC, Roberts EW, Blyth K, Coffelt SB, Carlin LM. Integrin inactivation slows down neutrophils congesting the pre-metastatic lung in a model of breast cancer. bioRxiv. 2024:2024.2003.2019.585724.
Fetit R, McLaren A, White M, Mills ML, Falconer J, Cortes-Lavaud X, Gilroy K, Lannagan TR, Ridgway RA, Nixon C, Naiker V, Njunge R, Clarke CJ, Whyte D, Kirschner K, Jackstadt R, Norman JC, Carlin LM, Campbell AD, Sansom OJ, Steele CW. Characterising neutrophil subtypes in cancer using scRNA sequencing demonstrates the importance of IL-1β/CXCR2 axis in generation of metastasis specific neutrophils. Cancer Res Commun. 2024.
2023
Koessinger D, Novo D, Koessinger A, Campos A, Peters J, Dutton L, Paschke P, Zerbst D, Moore M, Mitchell L, Neilson M, Stevenson K, Chalmers A, Tait S, Birch J, Norman J. Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness. Neuro-Oncology Advances. 2023;5:vdad067.
Moore M, Pardo L, Mitchell L, Schmidt T, May S, Mueller M, Strathdee D, Bryson S, Hodge K, Lilla S, Zanivan S, Waldron J, McGarry L, Peter-Durairaj R, Kanellos G, Nixon C, Ballantyne F, LeQuesne J, Sansom OJ, Bird T, Bushell M, Norman JC. The eIF4A2 negative regulator of mRNA translation promotes extracellular matrix deposition to accelerate hepatocellular carcinoma initiation. bioRxiv. 2023;Volume:2023.2008.2016.553544.
Nikolatou K, Sandilands E, Román-Fernández A, Cumming EM, Freckmann E, Lilla S, Buetow L, McGarry L, Neilson M, Shaw R, Strachan D, Miller C, Huang DT, McNeish IA, Norman JC, Zanivan S, Bryant DM. PTEN deficiency exposes a requirement for an ARF GTPase module for integrin-dependent invasion in ovarian cancer. The EMBO Journal. 2023;n/a:e113987.
Román-Fernández A, Mansour MA, Kugeratski FG, Anand J, Sandilands E, Galbraith L, Rakovic K, Freckmann EC, Cumming EM, Park J, Nikolatou K, Lilla S, Shaw R, Strachan D, Mason S, Patel R, McGarry L, Katoch A, Campbell KJ, Nixon C, Miller CJ, Leung HY, Le Quesne J, Norman JC, Zanivan S, Blyth K, Bryant DM. Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function. Sci Adv. 2023;9:eabq1858.
Waldron JA, Kanellos G, Smith RCL, Knight JRP, Munro J, Alexandrou C, Vlahov N, Pardo-Fernandez L, Moore M, Gillen SL, Strathdee D, Stevenson D, Warrander FC, Gilroy K, Nixon C, Cadden B, Powley I, Officer-Jones L, Ballantyne F, Hay J, Pennel K, Edwards J, Campbell AD, Ridgway RA, Coffelt SB, Norman J, Quesne JL, Bushell M, Sansom OJ. eIF4A1 is essential for reprogramming the translational landscape of Wnt-driven colorectal cancers. bioRxiv. 2023:2023.2011.2010.566546.
Wilson B, Flett C, Gemperle J, Lawless C, Hartshorn M, Hinde E, Harrison T, Chastney M, Taylor S, Allen J, Norman JC, Zacharchenko T, Caswell P. Proximity labelling identifies pro-migratory endocytic recycling cargo and machinery of the Rab4 and Rab11 families. J Cell Sci. 2023;136:jcs260468.
2022
Jamshidiha M, Lanyon-Hogg T, Sutherell CL, Craven GB, Tersa M, De Vita E, Brustur D, Pérez-Dorado I, Hassan S, Petracca R, Morgan RM, Sanz-Hernández M, Norman JC, Armstrong A, Mann DJ, Cota E, Tate EW. Identification of the first structurally validated covalent ligands of the small GTPase RAB27A. RSC Med Chem. 2022;13:150-155.
Koessinger AL, Cloix C, Koessinger D, Heiland DH, Bock FJ, Strathdee K, Kinch K, Martínez-Escardó L, Paul NR, Nixon C, Malviya G, Jackson MR, Campbell KJ, Stevenson K, Davis S, Elmasry Y, Ahmed A, O’Prey J, Ichim G, Schnell O, Stewart W, Blyth K, Ryan KM, Chalmers AJ, Norman JC, Tait SWG. Increased apoptotic sensitivity of glioblastoma enables therapeutic targeting by BH3-mimetics. Cell Death & Differentiation. 2022; 29: 2089–2104
Koessinger D, Novo D, Birch J, Mitchell L, Moore M, Zerbst D, Chalmers A, Koessinger A, Stevenson K, Nielson M, Norman JC. Glioblastoma exosomes influence glial cell hyaluronic acid deposition to promote invasiveness. bioRxiv. 2022;
Närvä E, Taskinen ME, Lilla S, Isomursu A, Pietilä M, Weltner J, Isola J, Sihto H, Joensuu H, Zanivan S, Norman J, Ivaska J. MASTL is enriched in cancerous and pluripotent stem cells and influences OCT1/OCT4 levels. iScience. 2022;25:104459.
Nikolatou K, Sandilands E, Roman-Fernandez A, Cumming EM, Freckmann EC, Lilla S, Buetow L, McGarry L, Neilson M, Shaw R, Strachan D, Miller C, Huang DT, McNeish IA, Norman JC, Zanivan S, Bryant D. PTEN deficiency exposes a requirement for an ARF GTPase module in integrin-dependent invasion in ovarian cancer. bioRxiv. 2022;Volume:2022.2011.2029.518198.
Rathan-Kumar S, Roland JT, Momoh M, Goldstein A, Lapierre LA, Manning E, Mitchell L, Norman J, Kaji I, Goldenring JR. Rab11FIP1-Deficient Mice Develop Spontaneous Inflammation and Show Increased Susceptibility to Colon Damage. Am J Physiol Gastrointest Liver Physiol. 2022; 323:G239-G254
2021
Mackey JBG, McFarlane AJ, Jamieson T, Jackstadt R, Raffo-Iraolagoitia XL, Secklehner J, Cortes-Lavaud X, Fercoq F, Clarke W, Hedley A, Gilroy K, Lilla S, Vuononvirta J, Graham GJ, De Filippo K, Murphy DJ, Steele CW, Norman JC, Bird TG, Mann DA, Morton JP, Zanivan S, Sansom OJ, Carlin LM. Maturation, developmental site, and pathology dictate murine neutrophil function. bioRxiv. 2021.
Marco S, Neilson M, Moore M, Perez-Garcia A, Hall H, Mitchell L, Lilla S, Blanco GR, Hedley A, Zanivan S, Norman JC. Nuclear-capture of endosomes depletes nuclear G-actin to promote SRF/MRTF activation and cancer cell invasion. Nat Commun. 2021 Nov 24;12(1):6829.
Nászai M, Bellec K, Yu Y, Román-Fernández A, Sandilands E, Johansson J, Campbell AD, Norman JC, Sansom OJ, Bryant DM, Cordero JB. RAL GTPases mediate EGFR-driven intestinal stem cell proliferation and tumourigenesis. Elife. 2021;10.
Phatak V, von Grabowiecki Y, Janus J, Officer L, Behan C, Aschauer L, Pinon L, Mackay H, Zanivan S, Norman JC, Kelly M, Le Quesne J, Muller PAJ. Mutant p53 promotes RCP-dependent chemoresistance coinciding with increased delivery of P-glycoprotein to the plasma membrane. Cell Death Dis. 2021;12(2):207.
Rabas N, Palmer S, Mitchell L, Ismail S, Gohlke A, Riley JS, Tait SWG, Gammage P, Soares LL, Macpherson IR, Norman JC. PINK1 drives production of mtDNA-containing extracellular vesicles to promote invasiveness. J Cell Biol. 2021;220:e202006049
Jackstadt R, Norman JC. Stromal WNTer Keeps the Tumor Cold and Drives Metastasis. Dev Cell. 2021;56:3-4.
2020
Koessinger AL, Koessinger D, Stevenson K, Cloix C, Mitchell L, Nixon C, Gomez-Roman N, Chalmers AJ, Norman JC, Tait SWG. Quantitative in vivo bioluminescence imaging of orthotopic patient-derived glioblastoma xenografts. Scientific Reports. 2020;10(1):15361.
Sundararaman A, Fukushima Y, Norman JC, Uemura A, Mellor H. RhoJ Regulates α5β1 Integrin Trafficking to Control Fibronectin Remodeling during Angiogenesis. Current Biology. 2020; 30: 2146 - 2155.e5
Taskinen ME, Närvä E, Conway JRW, Hinojosa LS, Lilla S, Mai A, De Franceschi N, Elo LL, Grosse R, Zanivan S, Norman JC, Ivaska J. MASTL promotes cell contractility and motility through kinase-independent signaling. J Cell Biol. 2020; 219: e201906204.
2019
Auciello FR, Bulusu V, Oon C, Tait-Mulder J, Berry M, Bhattacharyya S, Tumanov S, Allen-Petersen BL, Link J, Kendsersky ND, Vringer E, Schug M, Novo D, Hwang RF, Evans RM, Nixon C, Dorrell C, Morton JP, Norman JC, Sears RC, Kamphorst JJ, Sherman MH. A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression. Cancer Discov. 2019; 9: 617-627
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
Linnane E, Davey P, Zhang P, Puri S, Edbrooke M, Chiarparin E, Revenko AS, Macleod AR, Norman JC, Ross SJ. Differential uptake, kinetics and mechanisms of intracellular trafficking of next-generation antisense oligonucleotides across human cancer cell lines. Nucleic Acids Res. 2019; 47: 4375–4392
2018
Dornier E, Norman JC. Cancer cells with trapped nuclei cut their way through the extracellular matrix. Nat Commun 2018; 9: 3954
Novo D, Heath N, Mitchell L, Caligiuri G, MacFarlane A, Reijmer D, Charlton L, Knight J, Calka M, McGhee E, Dornier E, Sumpton D, Mason S, Echard A, Klinkert K, et al. Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels. Nat Commun 2018; 9: 5069.
2017
Diaz-Vera J, Palmer S, Hernandez-Fernaud JR, Dornier E, Mitchell LE, MacPherson I, Edwards J, Zanivan S, Norman JC. A proteomic approach to identify endosomal cargoes controlling cancer invasiveness. J Cell Sci 2017; 130: 697-711
Dornier E, Rabas N, Mitchell L, Novo D, Dhayade S, Marco S, Mackay G, Sumpton D, Pallares M, Nixon C, Blyth K, MacPherson I, Rainero E, Norman JC. Glutaminolysis drives membrane trafficking to promote cancer invasion. Nat Comms 2017; 8: 2255
Gundry C, Marco S, Rainero E, Miller B, Dornier E, Mitchell L, Caswell PT, Campbell AD, Hogeweg A, Sansom OJ, Morton JP, Norman JC. Phosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion. Nat Commun 2017; 8: 14646
Hall PS, Smith A, Hulme C, Vargas-Palacios A, Makris A, Hughes-Davies L, Dunn JA, Bartlett JMS, Cameron DA, Marshall A, Campbell A, Macpherson IR, Dan Rea, Francis A, Earl H, Morgan A, Stein RC, McCabe C; OPTIMA Trial Management Group. Value of information analysis of multiparameter tests for chemotherapy in early breast cancer: The OPTIMA Prelim Trial. Value Health 2017; 20: 1311-8
Hernandez-Fernaud JR, Ruengeler E, Casazza A, Neilson LJ, Pulleine E, Santi A, Ismail S, Lilla S, Dhayade S, MacPherson IR, McNeish I, Ennis D, Ali H, Kugeratski FG, Al Khamici H, van den Biggelaar M, van den Berghe PV, Cloix C, McDonald L, Millan D et al. Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity. Nat Commun 2017; 8: 14206
Dornier E, Norman JC. Tensin links energy metabolism to extracellular matrix assembly. J Cell Biol 2017; 216: 867-9
Norman J, Zanivan S. Chloride intracellular channel 3: A secreted pro-invasive oxidoreductase. Cell Cycle 2017; 16: 1993-4
2016
Birch J, Clarke CJ, Campbell AD, Campbell K, Mitchell L, Liko D, Kalna G, Strathdee D, Sansom OJ, Neilson M, Blyth K, Norman JC. The initiator methionine tRNA drives cell migration and invasion leading to increased metastatic potential in melanoma. Biol Open. 2016; 5: 1371-9
Boulay PL, Mitchell L, Turpin J, Huot-Marchand JE, Lavoie C, Sanguin-Gendreau V, Jones L, Mitra S, Livingstone JM, Campbell S, Hallett M, Mills GB, Park M, Chodosh L, Strathdee D, Norman JC, Muller WJ. Rab11-FIP1C is a critical negative regulator in ErbB2-mediated mammary tumor progression. Cancer Res. 2016; 76: 2662-74
Clarke CJ, Berg TJ, Birch J, Ennis D, Mitchell L, Cloix C, Campbell A, Sumpton D, Nixon C, Campbell K, Bridgeman VL, Vermeulen PB, Foo S, Kostaras E, Jones JL, Haywood L, Pulleine E, Yin HB, Strathdee D, Sansom O Blyth K, McNeish I, Zanivan S, Reynolds AR, Norman JC. The initiator methionine tRNA drives secretion of type II collagen from stromal fibroblasts to promote tumor growth and angiogenesis. Curr Biol. 2016; 26: 755-65
Lab Members
Associate Scientist
Cassie Clarke
Postdoctoral Scientists
Vanessa Gonzalez
Luis Pardo-Fernandez
Declan Whyte
Principal Scientific Officer
Madeleine Moore
Associate Clinical Scientist
Iain MacPherson
Clinical Research Fellow
Sonam Ansel
PhD Students
Sophie Fisher
Jasmine Peters (joint with Ed Roberts)
Lucy Somerville
