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Targeting developmental cell states in melanoma

针对黑色素瘤的发育细胞状态

基本信息

批准号：
MC_UU_00035/13
负责人：
Elizabeth Patton
金额：
$ 418.83万
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Intramural
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MC_UU_00035%2F13
关键词：
Targeting developmental cell states melanoma

项目摘要

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.

今年英国将有超过16，000人被诊断患有黑色素瘤，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是如何随着时间的推移对治疗产生耐药性的，并从长远来看，确定新的治疗靶点，改善人类健康。黑色素瘤来自我们的色素细胞，称为黑素细胞。我们和其他人最近发现，随着黑色素瘤细胞对治疗产生抗药性，它们会不适当地开启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。为了验证这一想法，我们将设计斑马鱼的遗传模型，因为我们可以直接跟踪黑色素瘤疾病的过程，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，并且一直是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我们的MRC人类遗传学单位的使命，通过使用先进的动物模型来解释基因是如何打开和关闭导致黑色素瘤耐药性，以解决人类遗传疾病的基本机制。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Adult zebrafish as advanced models of human disease.

DOI：
10.1242/dmm.050351
发表时间：
2023-08-01
期刊：
Disease models & mechanisms
影响因子：
4.3
作者：
通讯作者：

Acetylation reprograms MITF target selectivity and residence time.

DOI：
10.1038/s41467-023-41793-7
发表时间：
2023-09-28
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Louphrasitthiphol, Pakavarin;Loffreda, Alessia;Pogenberg, Vivian;Picaud, Sarah;Schepsky, Alexander;Friedrichsen, Hans;Zeng, Zhiqiang;Lashgari, Anahita;Thomas, Benjamin;Patton, E. Elizabeth;Wilmanns, Matthias;Filippakopoulos, Panagis;Lambert, Jean-Philippe;Steingrimsson, Eirikur;Mazza, Davide;Goding, Colin R.
通讯作者：
Goding, Colin R.

Valuing peer review at Disease Models & Mechanisms

重视疾病模型的同行评审