Melanoma is the deadliest form of skin cancer. The NRP Melanoma Research Group is a collective association of researchers and clinicians from across the NRP (Norwich Research Park) with a common interest in melanoma research. The principle role of the group is to bring together investigators from basic and translational research to foster scientific collaboration, and provide a platform for multidisciplinary projects into melanoma research within the NRP. The overall aim is that such projects will lead to the development of novel therapeutic strategies for melanoma patients.
Past Melanoma meetings:
10th December 2013 SCI 0.31 18.30 pm: 'Discovering novel anti-melanoma drugs using developmental biology' by Dr. Grant Wheeler (BIO).
25th June 2013 - 'The treatment of in-transit metastasis in melanoma patients' - Mr Marc Moncrieff.
11th December 2012 - click here for details.
Dr Francesca Baldelli Bombelli
The use of nanotechnology in medicine represents one of the most exciting developments in science over the last decade. In the NRP there is a team of researchers who are working to develop and validate a multi-modal therapy for the treatment of metastatic melanoma using multifunctional nanoparticles. These engineered NPs will combine targeting, imaging, chemotherapy and thermotherapy abilities in one single object. If successful this project will provide a directed multi-modal therapy to efficiently inhibit diverse essential biological processes for melanoma cell survival/progression by overcoming MDR. Even though significant progress has been made in NP engineering in terms of size, shape and surface functionalization, NP behaviour in vivo remains poorly characterized. In order to understand the potential impact of engineered nanomaterials on human health, it is fundamental to fully characterize them in relevant biological fluids. When in contact with biological fluids, NPs spontaneously interact and adsorb proteins forming what is known as the protein ‘corona' (PC), which dramatically changes their surface properties. Our research aims to elucidate the mechanism of formation of PC NPs in biological fluids relevant to the tumour microenvironment with particular care in the understanding of the extrinsic function of the corona by using phage-display libraries. We chose melanoma as a model system as we are developing in-house targeted NPs for melanoma treatment as well as we have access to fresh metastasized lymph nodes from which we can obtain a conditioned media from primary metastatic tumour tissues.
Dr Andrew Chantry
A hallmark of aggressive melanoma is that it spreads to other parts of the body, most often the lungs, liver, brain and bone. A key trigger for this transition from a pre-malignant skin cell to an aggressive and highly motile melanoma often involves spontaneous changes in the activity of cellular growth regulatory networks. Recently, we have been studying a gene subfamily that controls both the growth and spread of cancer cells. We have found that this group of enzymes attack and break down natural metastasis/growth inhibitors in the body known as Smads. Understanding how this process works could lead to the development of a next generation of drugs, as well as new prognostic tools that we hope will allow more precise monitoring of the different stages and types of melanoma and other types of cancer. Our approach involves state-of-the-art cancer cell/molecular technologies, that also encompasses structure-based design to target enzyme catalytic domains and key protein-protein interaction surfaces. We collaborate with Structural Biologists and Organic Chemists across the NRP, and will be exploring new technologies in the future for delivering peptide mimetics to intracellular targets inside cancer cells.
Prof Dylan Edwards
I am a molecular biologist principally interested in the functions of the "degradome" – the repertoire of proteases and their inhibitors that cells and tissues use during tissue remodelling processes in development, tissue repair and disease states. A major focus of the work of the laboratory is on cancer, where we are studying proteases to identify novel diagnostic markers and therapeutic targets, and to identify the cellular and molecular mechanisms of extracellular proteases. I was Coordinator of the European Union Framework Programme 6 "Cancerdegradome" Project, which involved 41 Partner laboratories in 13 countries, and is currently a partner in the FP7 "SaveMe" project on pancreatic cancer imaging and therapy using nanoparticles. Active research projects include:
- Extracellular matrix adhesion, signalling and proteolytic remodelling in angiogenesis
- Investigation of the roles of ADAM proteases in cell signalling
- Molecular mechanisms of transcriptional and post-transcriptional control of degradome gene expression
- Novel cancer therapies or chemopreventive agents, focussing on dietary phytonutrients
Dr Laszlo Igali
Melanoma-related interests: development and natural history of metastatic malignant melanoma, prognostic indicators in malignant melanoma, developing and using of dual immune-stains in assessment of prognostic factors (proliferation, lymphatic invasion), role of matrix metalloproteniases in metastasis production, role of the lipoxigenase and lipid byproducts in melanoma metastasis, signalling in malignant melanoma, use of BRAF immunostain in melanoma, molecular typing of malignant melanoma. My main interest is the development of metastatic disease, specifically the molecular and signalling pathways involved in the later stages of the disease – with particular interest in the phenotypical and genotypical changes of melanoma cells during disease progression. Also, the morphological manifestation of the molecular mechanisms, detection of the prognostic features and their correlation histopathology are also within my interest. Immunological mechanisms involved in regression and melanoma elimination, the relationship between the development of malignant melanoma and melanocytic senescence are also part of my interest.
Mr Marc Moncrieff
Surgical Oncology: Clinical trials for cutaneous melanoma, primary and metastatic, UK lead for 2 phase III multicentre trials. Oncology diagnostics: currently two Phase II studies, investigating accurate diagnosis & location of sentinel nodes in melanoma. Biobanking: Major interest in biobanking melanoma for genomic research. Basic Science research: collaboration with UEA investigating nanoparticle technology for chemotherapy delivery to advanced melanoma.
Dr Chris Morris
I am interested in the application of phage display technology for the screening of metastatic melanoma cell surfaces, with the aim of identifying novel cell-specific ligands. We are currently using peptide phage libraries to identify specific ligands for melanoma cells purified from sentinel lymph node tissue samples. Peptide ligands isolated from the libraries can both reveal the identity of novel melanoma biomarkers and serve as targeting moieties for diagnostic or therapeutics modalities such as nanoparticles.
Dr Darren Sexton
Together with collaborators I am interested in the flow cytometric detection of melanoma cells and identification of subtypes within these populations using flow cytometry and or single cell gene expression profiling. I am also interested in the cell death mechanisms induced by putative melanoma therapeutics.
Dr Vicky Sherwood
I work on understanding the molecular mechanisms that underpin the metastatic process in melanoma. Specifically my lab are studying metabolic behaviours arising in response to cell signalling cues, which fuel high migratory phenotypes in melanoma cells. One signalling pathway that we have been concentrating on for a number of years is the Wnt signalling pathway, which has long been linked to tumourigenesis in a number of cancers (including melanoma). We are interested in using this information to develop novel therapeutics for the treatment of late stage melanoma, which in collaboration with a number of other researchers across the NRP (and beyond), include the development of melanoma cell targeted-nanoscopic agents.
Dr Grant Wheeler
My lab works on the molecular events that govern the origin and migration of different cell types within the developing embryo. In particular we are studying the Neural Crest. These are a multipotent embryonic cells which give rise to the muscle and cartilage of the face, the peripheral nervous system and pigment cells. We have been carrying out chemical screens for a number of years identifying small molecules that interfere with pigment cell development and migration. Pigment cells when mutated give rise to melanoma so as part of these screens we have also identified small molecules that affect melanoma growth. One compound we have identified is currently undergoing clinical trials.
Selected publications by the group
Sherwood, V., Chaurasiya, S., Ekström, E., Guilmain, W., Liu, Q., Koeck, T., Brown, K., Hansson, K., Agnarsdóttir, M., Bergqvist, M., Jirström, K., Ponten, F., James, P., and Andersson, T.
WNT5A-Mediated ß-Catenin-Independent Signalling is a Novel Regulator of Cancer Cell Metabolism.
Carcinogenesis, 2013, In Press
Baldelli Bombelli F., Webster C., Moncrieff M. and Sherwood V.
The Scope of Nanoparticle Therapies for the Future of Metastatic Melanoma Treatment.
The Lancet Oncology, 2013, in press.
Soond, S, Smith, PG, Wahl, LC, Swingler, TE, Clark, IM, Hemmings, AM and Chantry
A Distinct roles for WWP2 ubiquitin ligase isoforms as potential prognostic markers and molecular targets in cancer
submitted to BBA, Molecular Basis of Disease, 2013, in press.
Leivonen S-K; Lazaridis K; Decock J; Chantry A; Edwards DR and Kähäri V-M
TGF-β-elicited induction of Tissue Inhibitor of Metalloproteinases (TIMP)-3 expression in fibroblasts involves complex interplay between Smad3, p38α and ERK1/2.
PLoS One, 2013 8:e57474.
Thirkettle S, Decock J, Arnold H, Pennington CJ, Jaworski DM and Edwards DR.
Matrix metalloproteinase-8 (collagenase-2) induces the expression of interleukins-6 and -8 in breast cancer cells.
J. Biol Chem, 2013, 282: 16282-16294.
Wills QF, Livak KJ, Tipping AJ, Enver T, Goldson AJ, Sexton DW, Holmes C.
Single-cell gene expression analysis reveals genetic associations masked in whole-tissue experiments.
Nature Biotechnology, 2013, 31, 748–752
Livak KJ, Wills QF, Tipping AJ, Datta K, Mittal R, Goldson AJ, Sexton DW, Holmes CC.
Methods for qPCR gene expression profiling applied to 1440 lymphoblastoid single cells.
Methods. 2013; 59(1):71-9.
Sonia Liggi, Georgios Drakakis, Adam E. Hendry, Kimberley M. Hanson, Suzanne C. Brewerton, Grant N. Wheeler, Michael J. Bodkin, David A. Evans, Andreas Bender.
Extensions to In Silico Bioactivity Predictions Using Pathway Annotations and Differential Pharmacology Analysis: Application to Xenopus laevis Phenotypic Readouts.
Molecular Informatics, 2013. Manuscript in press.
Pitek A.S., O'Connell D., Mahon E., Monopoli M.P., Baldelli Bombelli F*, Dawson K.A.
Transferrin Coated Nanoparticles: Study of the Bionano Interface in human plasma.
PLoS ONE, 2012, 7(7): e40685
Fawzy M, Garioch J, Igali L, Skrypniuk JV, Moncrieff MD.
Setting up an effective and efficient sentinel node biopsy service for malignant melanoma within the NHS.
J Plast Reconstr Aesthet Surg. 2012;65(3):351-5.
Smith, PG, Tanaka, H, and Chantry, A
A novel co-operative mechanism linking TGFß and Lyn kinase activation to imatinib resistance in chronic myeloid leukaemia cells
Oncotarget, 2012 3(5):518-24.
Azimi F, Scolyer RA, Rumcheva P, Moncrieff M, Murali R, McCarthy SW, Saw RP, Thompson JF.
Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma.
J.Clin Oncol. 2012,20;30(21):2678-83.
Matthew L. Tomlinson, Adam Hendry and Grant N. Wheeler.
Chemical genetics and drug discovery in Xenopus.
Methods Mol Biol, 2012,. 917:155-166
Grant N. Wheeler and Karen J. Liu.
Xenopus: an ideal system for chemical genetics.
Genesis, 2012, 50(3):207-18.
Monopoli M.P., Walczyk D., Campbell A., Elia G., Lynch I., Baldelli Bombelli F., Dawson K.A.
Physico-chemical aspects of protein corona: relevance in vitro and in vivo biological impacts of nanoparticles.
JACS, 2011, 133, 2525-2534.
Soond, S., and Chantry, A.
Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFß signalling and EMT.
Oncogene, 2011, 30, 2451-2462.
WWP2 ubiquitin ligase and its isoforms: New biological insight and promising disease targets.
Cell Cycle, 2011, 10(15), 2437-2439.
Cutts, A., Soond, S., Powell, S., and Chantry, A.
Early phase TGFß receptor signalling dynamics stabilised by the deubiquitinase UCH37 promotes cell migratory responses.
International Journal of Biochemistry and Cell Biology, 2011, 43, 604-612.
Soond, S., and Chantry, A.
How ubiquitination regulates the TGF-β signalling pathway: new insights and new players: new isoforms of ubiquitin-activating enzymes in the E1-E3 families join the game.
Bioessays, 2011, 33(10), 749-758.
Decock J, Thirkettle S, Wagstaff L and Edwards DR.
Matrix metalloproteinases: protective roles in cancer.
J. Cell Mol. Med, 2011. 15: 1254-1265.
Stuchinskaya T, Moreno M, Cook MJ, Edwards DR and Russell DA.
Targeted photodynamic therapy of breast cancer cells using antibody- phthalocyanine gold nanoparticle conjugates.
Photochemical and Photobiological Sciences, 2011, 10: 822-831.
Ekström, E., Sherwood, V., & Andersson, T.
Lack of secreted frizzled-related protein 3 expression increases cell migration and invasion in malignant melanoma.
PlosOne, 2011, 6(4):e18674.
White RM, Cech J, Ratanasirintrawoot S, Lin CY, Rahl PB, Burke CJ, Langdon E, Tomlinson ML, Mosher J, Kaufman C, Chen F, Long HK, Kramer M, Datta S, Neuberg D, Granter S, Young RA, Morrison S, Wheeler GN, Zon LI.
DHODH modulates transcriptional elongation in the neural crest and melanoma.
Nature, 2011, 471:518-22
Stokes A, Joutsa J, Ala-aho R, Pitchers M, Pennington CJ, Martin C, Premachandra DJ, Okada Y, Peltonen J, Grénman R, James HA, Edwards DR and Kähäri V-M.
Expression profiles and clinical correlations of degradome components in the tumor microenvironment of head and neck squamous cell carcinoma.
Clinical Cancer Res, 2010, 16: 2022-2035.
Atkinson JM, Loadman PM, Falconer RA, Edwards DR, Pennington CJ, Patterson LH, Shnyder SD and Gill JH.
Development of a tumour-targeted vascular disrupting agent activated by MT-MMPs.
Cancer Res, 2010,70: 6902-6912.
Emery JD, Hunter J, Hall PN, Watson AJ, Moncrieff M, Walter FM.
Accuracy of SIAscopy for pigmented skin lesions encountered in primary care: development and validation of a new diagnostic algorithm.
BMC Dermatol. 2010, 25;10:9.
Murali R, Moncrieff MD, Hong J, Cooper CL, Shingde MV, Samuel DG, Thompson JF, Scolyer RA.
The prognostic value of tumor mitotic rate and other clinicopathologic factors in patients with locoregional recurrences of melanoma.
Ann Surg Oncol. 2010;17(11):2992-9.
Patel NG, Shah AK, Barker T, Garioch J, Moncrieff MD.
Malignant melanoma re-excision specimens: the need for analysis.
J Plast Reconstr Aesthet Surg. 2010 Aug;63(8):e653-4.
Moncrieff MD, Thompson JF, Stretch JR.
Extended experience and modifications in the design and concepts of the keystone design island flap.
J Plast Reconstr Aesthet Surg. 2010; 63(8):1359-63.
Moncrieff MD, Spira K, Clark JR, Thompson JF, Clifford AR, O'Brien CJ, Shannon KF.
Free flap reconstruction for melanoma of the head and neck: indications and outcomes.
J Plast Reconstr Aesthet Surg. 2010;63(2):205-12.
Morris CJ, Smith MW, Griffiths PC, McKeown NB, Gumbleton M.
Enhanced pulmonary absorption of a macromolecule through coupling to a sequence-specific phage display-derived peptide.
J Control Release, 2011, 151, 1, 83–94
Recino, A., Sherwood, V., Flaxman, A., Cooper, W., Latif, F., Ward, A., & Chalmers, A. D.
Human RASSF7 regulates the microtubule cytoskeleton and is required for spindle formation, Aurora B activation and chromosomal congression during mitosis.
Biochemical Journal, 2010, 430: 207-213.
Sherwood, V., Recino, A., Jeffries, A., Ward, A., & Chalmers, A. D.
The N-terminal RASSF family; A new group of Ras association domain containing proteins, with emerging links to cancer formation.
Biochemical Journal, 2010, 425, 303-311.
Pais, H., Nicolas, F.E., Soond, S.M., Swingler, T.E., Clark, I.M., Chantry, A., Moulton, V.E., and Dalmay, T.
Analysing mRNA expression identifies Smad3 as a microRNA-140 target regulated only at protein level.
RNA, 2009, 16, 489-494.
Sanki A, Uren RF, Moncrieff M, Tran KL, Scolyer RA, Lin HY, Thompson JF.
Targeted high-resolution ultrasound is not an effective substitute for sentinel lymph node biopsy in patients with primary cutaneous melanoma.
J Clin Oncol, 2009 20;27(33):5614-9.
Murali R, Cochran AJ, Cook MG, Hillman JD, Karim RZ, Moncrieff M, Starz H, Thompson JF, Scolyer RA.
Interobserver reproducibility of histologic parameters of melanoma deposits in sentinel lymph nodes: implications for management of patients with melanoma.
Cancer. 2009 1;115(21):5026-37.
Moncrieff MD, Thompson JF, Quinn MJ, Stretch JR.
Reconstruction after wide excision of primary cutaneous melanomas: part I-the head and neck.
Lancet Oncol. 2009;10(7):700-8.
Kroon HM, Moncrieff M, Kam PC, Thompson JF.
Factors predictive of acute regional toxicity after isolated limb infusion with melphalan and actinomycin D in melanoma patients.
Ann Surg Oncol. 2009 May;16(5):1184-92.
Jenei, V.*, Sherwood, V.*, Howlin, J., Linnskog, R., Säfholm, A., Axelsson, L., & Andersson, T.
A t-butyloxycarbonyl-modified Wnt5a-derived hexapeptide functions as a potent antagonist of Wnt5a-dependent melanoma cell invasion.
Proc. Nat. Acad. Sci, 2009, USA 106, 19473-19478. (*Both authors contributed equally to this work).
Grant N. Wheeler and Andre Brandlii.
Simple vertebrate models for chemical genetics and drug discovery screens: lessons from zebrafish and Xenopus.
Dev Dyn, 2009, 238:1287-1308.
Matthew L. Tomlinson, Martin Rejzek, Mark Fidock, Robert A. Field and Grant N. Wheeler.
Chemical genomics identifies compounds affecting Xenopus laevis pigment cell development.
Molecular BioSystems, 2009, 5:376-384
Matthew L. Tomlinson, Pingping Guan, Richard J. Morris, Mark Fidock, Martin Rejzek, Carla Garcia-Morales, Robert A. Field and Grant N. Wheeler.
A chemical genomic approach identifies matrix metalloptroteinases as playing an essential and specific role in Xenopus melanophore migration.
Chemistry and Biology, 2009, 16:1-12
Frost, V., Grocott, T., Eccles, M.R. and Chantry, A.
Self-regulated Pax gene expression and modulation by the ßTGF superfamily.
Critical Reviews in Biochemistry and Molecular Biology, 2008, Nov-Dec, 43(6), 371-391.
Traka, M., Gasper, A.V., Melchini, A., Bacon, J.R., Needs, P.W., Frost, V., Chantry, A., Jones, A.M., Ortori, C.A., Barrett, D.A., Ball, R.Y., Mills, R.D., and Mithen, R.F.
Broccoli Consumption Interacts with GSTM1 to Perturb Oncogenic Signalling Pathways in the Prostate.
PLoS ONE. 2008, Jul 2;3(7): e2568.
Gutiérrez-Fernández A, Fueyo A, Folgueras AR, Garabaya C, Pennington CJ, Pilgrim S, Edwards DR, Holliday DL, Jones JL, Span PN, Sweep FCGJ, Puente XS and López-Otín C.
Collagenase-2 (MMP-8) functions as a metastasis suppressor through modulation of tumor cell adhesion and invasiveness.
Cancer Res, 2008, 68: 2755-2763.
Moncrieff MD, Martin R, O'Brien CJ, Shannon KF, Clark JR, Gao K, McCarthy WM, Thompson JF.
Adjuvant postoperative radiotherapy to the cervical lymph nodes in cutaneous melanoma: is there any benefit for high-risk patients?
Ann Surg Oncol. 2008 Nov;15(11):3022-7.
Moncrieff M, Scolyer R, Thompson J, Beavis A, Uren R, Stretch J.
Correct identification of a sentinel node post selective lymphadenectomy using antimony levels.
Melanoma Res. 2008 Oct;18(5):365-6.
Moncrieff MD, Bowen F, Thompson JF, Saw RP, Shannon KF, Spillane AJ, Quinn MJ, Stretch JR.
Keystone flap reconstruction of primary melanoma excision defects of the leg-the end of the skin graft?
Ann Surg Oncol. 2008 Oct;15(10):2867-73.
Kroon HM, Moncrieff M, Kam PC, Thompson JF.
Outcomes following isolated limb infusion for melanoma. A 14-year experience.
Ann Surg Oncol. 2008 Nov;15(11):3003-13.
Moncrieff M, Shannon K, Hong A, Hersey P, Thompson J.
Dramatic reduction of chronic lymphoedema of the lower limb with sorafenib therapy.
Melanoma Res. 2008 Apr;18(2):161-2.
Sherwood, V., Manbodh, R., Sheppard, C., & Chalmers, A. D.
RASSF7 is a member of a new family of RAS association domain-containing proteins and is required for completing mitosis.
Molecular Biology of the Cell, 2008, 19, 1772-1782.
Matthew Tomlinson, Muhammad Abu-Elmagd, Carla Garcia-Morales and Grant N. Wheeler.
A combinatorial role for three matrix metalloproteinases in Xenopus macrophage migration.
Mechanism of Development, 2008, 125:1059-1070.