PROMINENT - UCSF

杰出 - UCSF

• 批准号: 10625150
• 负责人: ALLAN BALMAIN
• 金额: $ 126.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-22 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625150
• 关键词: Text

The cancer research community is on the verge of a major leap in our understanding of the factors that contribute to human cancer risk. While it is clear that mutations in DNA, either spontaneous or environmentally induced, are essential for cancer development, recent advances have highlighted the importance of non-mutagenic factors as rate-limiting determinants of cancer risk in human populations and in mouse cancer models. The root causes of human cancer have been widely debated, but most of the emphasis has been on the origins of the “driver” mutations that are ubiquitous in human tumours. Although epidemiology studies have highlighted the possible roles of lifestyle factors such as obesity, alcohol consumption, inflammation and poor diet in cancer risk, it has generally been assumed that these factors act directly or indirectly to cause mutations in DNA, thus contributing to tumour mutational burden and resulting in increased cancer risk. In contrast, recent sequencing studies have uncovered abundant mutations in normal human tissues, suggesting that even strong cancer driver mutations are not sufficient for cancer formation. These results were presaged by studies of mouse tumour models, some carried out more than 50 years ago, showing that promotion is the rate-limiting step in tumour development. To identify the mechanisms that control mutated normal cells, and to elucidate the precise mechanisms by which promoting factors stimulate the conversion of these cells to neoplastic growth, we have assembled a multidisciplinary team of investigators with wide-ranging experience in epidemiology, genetics, computational network analysis and machine learning, tissue imaging of gene expression, single cell transcriptomics, and genome-wide CRISPR functional screens. We will focus human analysis on a unique collection of several thousand human normal and matched tumour samples from >20 countries, including regions of both high and low cancer risk. Detailed risk factor information and whole genome sequence data is available from all these samples as part of the Grand Challenge Mutographs study. Analysis of these samples, together with detailed intervention studies in human populations, mouse models and human organoids, will allow us to develop a roadmap of tumour promotion from single normal cells carrying driver mutations, through to malignant progression. Our findings will facilitate identification of the causative environmental factors that promote cancer and provide routes to new methods and approaches to cancer prevention based on a deeper understanding of the process of initiated cell selection by tumour promoting agents.

癌症研究界即将在我们对导致人类癌症风险的因素的理解方面取得重大飞跃。虽然很明显，DNA突变，无论是自发的还是环境诱导的，对癌症的发展都是必不可少的，但最近的研究进展强调了非突变因素作为人类群体和小鼠癌症模型中癌症风险的限速决定因素的重要性。 人类癌症的根本原因一直被广泛辩论，但大部分的重点是在人类肿瘤中普遍存在的“驱动因素”突变的起源上。虽然流行病学研究强调了肥胖、饮酒、炎症和不良饮食等生活方式因素在癌症风险中的可能作用，但通常认为这些因素直接或间接地导致DNA突变，从而导致肿瘤突变负担并导致癌症风险增加。相比之下，最近的测序研究在正常的人类组织中发现了大量的突变，这表明即使是强烈的癌症驱动突变也不足以导致癌症的形成。对小鼠肿瘤模型的研究预示了这些结果，其中一些研究是在50多年前进行的，表明促进是肿瘤发展的限速步骤。 为了确定控制突变的正常细胞的机制，并阐明促进因子刺激这些细胞向肿瘤生长转化的确切机制，我们组建了一个多学科的研究团队，他们在流行病学、遗传学、计算网络分析和机器学习、基因表达的组织成像、单细胞转录和基因组范围的CRISPR功能筛选方面具有广泛的经验。我们将把人类分析的重点放在一组独特的人类正常和匹配的肿瘤样本上，这些样本来自20个国家，包括癌症风险高和低的地区。详细的风险因素信息和全基因组序列数据可以从所有这些样本中获得，作为大挑战Mutograph研究的一部分。对这些样本的分析，加上对人类种群、小鼠模型和人类有机体的详细干预研究，将使我们能够制定从携带驱动程序突变的单个正常细胞到恶性进展的肿瘤促进路线图。我们的发现将有助于识别促进癌症的致病环境因素，并基于对肿瘤促进剂启动细胞选择过程的深入了解，为癌症预防提供新的方法和途径。