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

老鼠经常被用作研究癌症的工具，包括恶性黑色素瘤，这是最致命的皮肤癌形式，也是英国第五大最常见的癌症，每年导致2000多人死亡。虽然局限于皮肤的黑色素瘤可以通过手术切除来治愈，但当肿瘤扩散到身体其他部位(转移)时，它是无法治愈的，这突显了迫切需要更好的方法来识别和治疗潜在的侵袭性肿瘤。虽然在研究中使用动物对提高我们对癌症生物学的理解以及开发治疗癌症的新药至关重要，但研究人员的目标是尽量减少在癌症研究中使用动物，并在可能的情况下开发替代方法，通过这些方法产生有意义的结果。因此，目前研究建议的主要目标是开发模型，以取代使用小鼠来研究黑色素瘤，特别是通过创建3D人类皮肤等效模型，重建皮肤的精确环境条件，以模拟黑色素瘤的早期发展和进展阶段，以及斑马鱼模型，模拟黑色素瘤在疾病后期在人体内的转移。一旦完全开发出来，这些模型将被用来回答重要的生物学问题，并产生至关重要的黑色素瘤新治疗策略。初步研究已经确定了一种特定的肿瘤细胞亚群(黑色素瘤干细胞)，它们能够自我更新并推动肿瘤进展。了解特定的细胞生存机制(自噬)如何有助于这些亚群的增长，将有助于开发新的治疗策略，并改善临床结果。

Mice are often used as a tool to investigate cancer, including malignant melanoma, the most deadly form of skin cancer, and the the 5th most common cancer in the UK, resulting in more than 2000 deaths annually. Although melanoma localised to the skin can be cured by surgical excision, when the tumour spreads to other parts of the body (metastasis) it is incurable, emphasising the acute need for better ways to identify and treat potentially aggressive tumours. While the use of animals in research is vital to improve our understanding of cancer biology, and to the development of new drugs to treat cancer, researchers nevertheless aim to minimise the use of animals in cancer research and wherever possible develop alternative ways through which to generate meaningful results. The principal goal of the current research proposal is therefore to develop models that replace the use of mice for the investigation of melanoma, specifically, by creating a 3D human skin equivalent model, that recreates the precise environmental conditions of the skin, to model the early stages of melanoma development and progression, as well as a zebrafish model that mimics metastasis of melanoma in the human body during later disease stages. When fully developed, these models will be used to answer important biological questions and generate crucially required novel treatment strategies for melanoma. Preliminary research has identified a particular subpopulation of tumour cells (melanoma stem-like cells) that are able to self-renew and drive tumour progression. Understanding how specific cell survival mechanisms (autophagy) contribute to the growth of these subpopulations, will enable the development of novel therapeutic strategies with improved clinical outcome.