BIOGRAPHY AND RESEARCH INTERESTS
ZFIN ID: ZDB-PERS-101004-2
July 2010 -
Lecturer, University of Manchester
July 2004 - June 2010
Cancer Research UK Career Development Fellow, University of Manchester
Post-doctoral research associate in the lab. of Hans Clevers, Academic Hospital Utrecht and Hubrecht Laboratories, The Netherlands
Wellcome Trust International Prize Travelling Fellow. Post-doctoral research performed in the lab. of Hans Clevers, Academic Hospital Utrecht, The Netherlands
PhD University of Glasgow, Faculty of Medicine. Research performed at CR-UK Beatson laboratories under the supervison of Dr Donald M. Black
BA (Hons) University of Cambridge, Natural Sciences.
The main focus of my group is tumour biology. In particular, we focus on chemotherapy resistance in cancer and factors underlying malignant conversion. Our chosen model is the zebrafish and we manipulate this organism using mutagenesis, transgenesis, antisense oligonucleotides, and small molecule inhibitors. Using these methods, we have developed several tumour models including melanoma and intestinal tumours, and are now validating the role of certain protein targets (implicated through transcription profiling and data mining) in therapeutic resistance and/or disease progression.
To illustrate our strategy, we have recently targeted expression of human oncogenic RAS to zebrafish melanocytes. This has given rise to a model of melanoma, both sporadic and familial. At the same time through expressing oncogenic BRAF, we have generated a model of benign melanocyte neoplasia. Moreover, through simultaneously expressing RAS and an inhibitor of the PI3K signalling pathway (a truncated form of the PI3K regulatory protein p85), we have demonstrated the importance of PI3K signalling in the progression of melanocyte neoplasia to malignancy. Comparing the transcriptomes of melanocytes with these different genotypes is revealing interesting patterns of diffferential gene expression that correlate with disease state. Analysis of these altered states of gene expression is implicating deregulated developmental signalling and inflammation in melanoma disease progression.
The above gene expression analysis is also supplying us with candidates to pursue to target melanoma. We have demonstrated that melanoma initiates in RAS-expressing animals soon after fertilisation. At this time-point animals are very amenable to targeted knockdown of gene products using both antisense oligonucleotides as well as small molecule inhibitors. We have developed a simple, sensitive and robust spectrophotometric assay for quantifying the extent of neoplasia in transgenic larval zebrafish, and have demonstrated that targeted knockdown of MAPK, PI3K and TOR signalling components antagonizes melanoma development. Reversing the logic of this approach implies that this in vivo assay could be used to discover novel antineoplastic compounds, something we would like to demonstrate in the near future.
Henderson, F., Johnston, H.R., Badrock, A.P., Jones, E.A., Forster, D., Nagaraju, R.T., Evangelou, C., Kamarashev, J., Green, M., Fairclough, M., Barinaga-Rementeria Ramirez, I., He, S., Snaar-Jagalska, B.E., Hollywood, K., Dunn, W.B., Spaink, H.P., Smith, M.P., Lorigan, P., Claude, E., Williams, K.J., McMahon, A.W., Hurlstone, A. (2019) Enhanced fatty acid scavenging and glycerophospholipid metabolism accompanies melanocyte neoplasia progression in zebrafish. Cancer research. 79(9):2136-2151
Crilly, S., Njegic, A., Laurie, S.E., Fotiou, E., Hudson, G., Barrington, J., Webb, K., Young, H.L., Badrock, A.P., Hurlstone, A., Rivers-Auty, J., Parry-Jones, A.R., Allan, S.M., Kasher, P.R. (2018) Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage. F1000Research. 7:1617
Casar, B., Badrock, A.P., Jiménez, I., Arozarena, I., Colón-Bolea, P., Lorenzo-Martín, L.F., Barinaga-Rementería, I., Barriuso, J., Cappitelli, V., Donoghue, D.J., Bustelo, X.R., Hurlstone, A., Crespo, P. (2018) RAS at the Golgi antagonizes malignant transformation through PTPRκ-mediated inhibition of ERK activation. Nature communications. 9:3595
Diamantopoulou, Z., White, G., Fadlullah, M.Z.H., Dreger, M., Pickering, K., Maltas, J., Ashton, G., MacLeod, R., Baillie, G.S., Kouskoff, V., Lacaud, G., Murray, G.I., Sansom, O.J., Hurlstone, A.F.L., Malliri, A. (2017) TIAM1 Antagonizes TAZ/YAP Both in the Destruction Complex in the Cytoplasm and in the Nucleus to Inhibit Invasion of Intestinal Epithelial Cells. Cancer Cell. 31:621-634.e6
Dee, C.T., Nagaraju, R.T., Athanasiadis, E.I., Gray, C., Fernandez Del Ama, L., Johnston, S.A., Secombes, C.J., Cvejic, A., Hurlstone, A.F. (2016) CD4-Transgenic Zebrafish Reveal Tissue-Resident Th2- and Regulatory T Cell-like Populations and Diverse Mononuclear Phagocytes. Journal of immunology (Baltimore, Md. : 1950). 197(9):3520-3530
Fernandez Del Ama, L., Jones, M., Walker, P., Chapman, A., Braun, J.A., Mohr, J., Hurlstone, A.F. (2016) Reprofiling using a zebrafish melanoma model reveals drugs cooperating with targeted therapeutics. Oncotarget. 7(26):40348-40361
Paul, N.R., Allen, J.L., Chapman, A., Morlan-Mairal, M., Zindy, E., Jacquemet, G., Fernandez del Ama, L., Ferizovic, N., Green, D.M., Howe, J.D., Ehler, E., Hurlstone, A., Caswell, P.T. (2015) α5β1 integrin recycling promotes Arp2/3-independent cancer cell invasion via the formin FHOD3. The Journal of cell biology. 210:1013-31
Herrero, A., Pinto, A., Colón-Bolea, P., Casar, B., Jones, M., Agudo-Ibáñez, L., Vidal, R., Tenbaum, S.P., Nuciforo, P., Valdizán, E.M., Horvath, Z., Orfi, L., Pineda-Lucena, A., Bony, E., Keri, G., Rivas, G., Pazos, A., Gozalbes, R., Palmer, H.G., Hurlstone, A., Crespo, P. (2015) Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes. Cancer Cell. 28:170-82
Chapman, A., Fernandez Del Ama, L., Ferguson, J., Kamarashev, J., Wellbrock, C., Hurlstone, A. (2014) Heterogeneous Tumor Subpopulations Cooperate to Drive Invasion. Cell Reports. 8(3):688-695
Burgon, J., Robertson, A.L., Sadiku, P., Wang, X., Hooper-Greenhill, E., Prince, L.R., Walker, P., Hoggett, E.E., Ward, J.R., Farrow, S.N., Zuercher, W.J., Jeffrey, P., Savage, C.O., Ingham, P.W., Hurlstone, A.F., Whyte, M.K., and Renshaw, S.A. (2014) Serum and Glucocorticoid-Regulated Kinase 1 Regulates Neutrophil Clearance during Inflammation Resolution. Journal of immunology (Baltimore, Md. : 1950). 192(4):1796-1805
Dalton, L.E., Kamarashev, J., Ramirez, I.R., White, G., Malliri, A., and Hurlstone, A. (2013) Constitutive Rac Activation is not Sufficient to Initiate Melanocyte Neoplasia but Accelerates Malignant Progression. The Journal of investigative dermatology. 133(6):1572-81
Smith, M.P., Ferguson, J., Arozarena, I., Hayward, R., Marais, R., Chapman, A., Hurlstone, A., and Wellbrock, C. (2013) Effect of SMURF2 Targeting on Susceptibility to MEK Inhibitors in Melanoma. Journal of the National Cancer Institute. 105(1):33-46
Ramirez, I.B., Pietka, G., Jones, D.R., Divecha, N., Aliam, A., Baraban, S.C., Hurlstone, A.F., and Lowe, M. (2012) Impaired Neural Development in a Zebrafish Model for Lowe Syndrome. Human molecular genetics. 21(8):1744-1759
Haud, N., Kara, F., Diekmann, S., Henneke, M., Willer, J.R., Hillwig, M.S., Gregg, R.G., Macintosh, G.C., Gärtner, J., Alia, A., and Hurlstone, A.F. (2011) rnaset2 mutant zebrafish model familial cystic leukoencephalopathy and reveal a role for RNase T2 in degrading ribosomal RNA. Proceedings of the National Academy of Sciences of the United States of America. 108(3):1099-1103
Santoriello, C., Gennaro, E., Anelli, V., Distel, M., Kelly, A., Köster, R.W., Hurlstone, A., and Mione, M. (2010) Kita Driven Expression of Oncogenic HRAS Leads to Early Onset and Highly Penetrant Melanoma in Zebrafish. PLoS One. 5(12):e15170
Michailidou, C., Jones, M., Walker, P., Kamarashev, J., Kelly, A., and Hurlstone, A.F. (2009) Dissecting the roles of Raf- and PI3K-signalling pathways in melanoma formation and progression in a zebrafish model. Disease models & mechanisms. 2(7-8):399-411