Targeting developmental cell states in melanoma

今年英国将有超过16000人被诊断为黑色素瘤，黑色素瘤现在是年轻人最常见的癌症之一。在过去的15年里，新的治疗方法改善了许多患者的预后，但仍然有近一半的转移性黑色素瘤患者死于这种疾病。我们的目标是了解黑色素瘤细胞如何随着时间的推移而对治疗产生耐药性，并从长远的角度确定新的治疗目标，改善人类健康。黑色素瘤起源于我们的色素细胞，称为黑素细胞。我们和其他人最近发现，当黑色素瘤细胞对治疗产生耐药性时，它们会不恰当地启动胚胎发育期间的基因。我们认为，采用这些胚胎特征，黑色素瘤细胞可以迅速适应和逃避治疗。为了验证这个想法，我们将设计斑马鱼的基因模型，因为我们可以直接跟踪黑色素瘤的发病过程，并在活体动物中执行干预策略。重要的是，斑马鱼黑色素瘤准确地模拟了人类黑色素瘤，并已成为药物发现和临床试验的基础。斑马鱼的新发现将在患者来源的样本中进行测试，以确保人类遗传疾病的相关性。我们的工作直接有助于MRC人类遗传学小组的使命，即通过使用先进的动物模型来解释基因如何开启和关闭以导致黑色素瘤耐药性，从而解决人类遗传疾病的基本机制。

Over 16,000 people in the UK will be diagnosed with melanoma this year, and melanoma is now one of the most common cancers in young adults. In the past 15 years, new therapies have improved outcomes for many patients, but still almost half of people with metastatic melanoma die from the disease. We aim to understand how melanoma cells become resistant to therapy over time, with the long-term view to identify new targets for therapies and improve human health. Melanoma arises from our pigment cells, called melanocytes. We and others have recently discovered that as melanoma cells become resistant to therapy, they inappropriately turn on genes from during embryonic development. We propose that adopting these embryonic characteristics, melanoma cells can rapidly adapt and escape therapy. To test this idea, we will engineer genetic models of zebrafish, because we can directly follow melanoma disease processes and perform intervention strategies in living animals. Importantly, zebrafish melanomas accurately model human melanoma and have been the basis of drug discovery and clinical trials. New findings in zebrafish will be tested in patient-derived samples to ensure human genetic disease relevance. Our work directly contributes towards our MRC Human Genetics Unit mission to address fundamental mechanisms of human genetic disease by using advanced animal models to interpret how genes are turned on and off to lead to melanoma drug resistance.