Contribution of autophagy to the maintenance, invasion and metastasis of melanoma stem-like sub populations.

Mouse models of cancer are a valuable tool for the investigation of tumour growth, progression and response to therapy. However, as these models likely cause pain and distress to the mouse, researchers have an obligation to minimise the use of mice, and if possible replace them with non-animal alternatives. The current proposal aims to develop and optimise two novel models, a 3D in vitro human melanoma skin equivalent (MSE) and an in vivo zebrafish xenograft of human melanoma, to replace the use of mice in research. Malignant melanoma is a growing world health concern, with an incidence that has risen more than any other malignancy in the last 40 years. Although curable by surgical resection at early disease stages, metastatic disease is highly invasive, and evolves with an extensive repertoire of molecular defences against immunological and cytotoxic attack, rendering this type of tumour, as yet, incurable. Targeting melanoma stem-like subpopulations, including those expressing stem cell markers CD271 and ABCB5, which constitute a self-renewing, tumour-maintaining subpopulation, that sustain melanoma growth and drive tumour progression, may represent a novel therapeutic strategy for melanoma. Since pilot data also suggests CD271/ABCB5 expressing melanoma subpopulations use autophagy, a critical recycling mechanism for the maintainence of cellular homeostasis, modulating autophagy may offer a novel therapeutic approach to target these cells. This project will thus use the developed MSE and zebrafish xenograft models of human melanoma to test the hypothesis that autophagy contributes to the maintenance, invasiveness and metastatic potential of CD271/ABCB5 expressing stem-like melanoma subpopulations.

Verykiou S et al. (2019). Harnessing autophagy to overcome mitogen-activated protein kinase kinase inhibitor-induced resistance in metastatic melanoma. The British Journal of Dermatology 180(2):346-356. doi: 10.1111/bjd.17333

Hill D et al. (2018). Embryonic zebrafish xenograft assay of human cancer metastasis. F1000Research 7:1682. doi: 10.12688/f1000research.16659.2

Beaumont KA et al. (2016). Cell cycle phase-specific drug resistance as an escape mechanism of melanoma cells. J Invest Dermatol 136(7):1479-89. doi: 10.1016/j.jid.2016.02.805 

Armstrong JL et al. (2015). Exploiting cannabinoid-induced cytotoxic autophagy to drive melanoma cell death. J Invest Dermatol 135(6):1629-1637. doi: 10.1038/jid.2015.45

Hill DS et al. (2015). A novel fully humanized 3D skin equivalent to model early melanoma invasion. Mol Cancer Ther 14(11):2665-73. doi: 10.1158/1535-7163.MCT-15-0394

Haass NK et al. (2014). Real-time cell cycle imaging during melanoma growth, invasion, and drug response. Pigment Cell & Melanoma Research 27(5):764-76. doi: 10.1111/pcmr.12274

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Fellowship

Status

Closed

Institution

Newcastle University

Grant reference number

NC/L002000/1

Award date

Sep 2014 - Aug 2017

Grant amount

£195,000