Genetic Modifiers of Intitiation and Progression of Mamm

Mamm 起始和进展的遗传修饰因素

• 批准号: 6954022
• 负责人: KENT William HUNTER
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6954022
• 关键词: animal population genetics; breast neoplasms; disease /disorder model; early diagnosis; gene expression; genetic mapping; genetic markers; genetic models; genetic susceptibility; genetically modified animals; inbreeding; laboratory mouse; metastasis; model design /development; neoplasm /cancer diagnosis; neoplasm /cancer genetics; neoplastic process; prognosis

The process of tumor dissemination or metastasis is an important aspect of clinical management of cancer. In most cases cancer patients with localized tumors have significantly better prognoses than those with disseminated tumors. The majority of cancer mortality has been associated with metastatic disease rather than the primary tumor. Since it has been estimated that 60-70% of patients have progressed to metastatic disease by the time of diagnosis better understanding of the factors leading to tumor dissemination is of vital importance. An enormous amount of research has been performed elucidating various components of this process. As a result a great deal is known about different molecules and pathways that are associated with metastatic progression, including activation of oncogenes, recruitment of metalloproteases, and motility factors. Metastasis-associated loss of heterozygosity has also been used as a tool to identify members of a class of genes known as the metastasis suppressors . To date eight members of this class of genes have been described: NM23, KISS1, KAI1, E-cadherin , MKK4, TIMPs, Maspin , BRMS1, RhoGDI2. Despite this wealth of information, the critical initiating events or molecular pathways for tumor dissemination remain unclear. Part of the difficulty unraveling the complexity of metastasis may be due to multiple converging pathways associated with malignant potential. Another confounding factor is likely to be genetic modulation of the efficiency of tumor dissemination. Identification of key regulatory components of the metastatic process would serve two functions. First, they might provide more accurate prognostic markers of potential metastatic progression in patients than the current standards. Second, they may provide insights into the critical events in tumor dissemination, potentially leading to additional avenues of research or the development of novel therapies. My laboratory uses animal models for gene discovery and/or test hypotheses that are difficult or impossible to do in human populations, including direct experimental testing of epidemiological correlations. The focus of my laboratory is a combined genetics and genomics approach to determine how constitutional genetic composition influences susceptibility to malignant progression. The model studied is the highly aggressive, metastatic transgenic mammary tumor FVB/N-TgN(MMTV-PyVT)634Mul mouse, which develops pulmonary metastatic lesions in ~85% of the animals by 100 days of age. By performing a breeding based strain survey, my laboratory demonstrated the first in vivo evidence that genetic background of the host is a major determinant of metastatic potential. Using quantitative trait genetic analysis of backcross or recombinant inbred mouse populations we subsequently mapped the location of at least two significant modifier genes and identified three other suggestive modifier genes. Currently my laboratory is applying both conventional mouse genetic and population-based strategies to attempt to identify and characterize the genes, pathways and polymorphisms that underlie the metastatic efficiency observed in the different genotypes. A two-prong strategy is being pursued. The first arm of the strategy is based on the conventional approach of developing interval specific congenic and subcongenic animals to generate a high-resolution mapping of the modifier genes followed by standard positional candidate strategies. While the conventional strategy has a high probability of success, it is a slow and laborious process that requires extensive animal breeding and manipulation. Therefore, in parallel with the conventional congenic based strategy, we are exploring alternative strategies for modifier candidate gene selection. For example, using latency as a phenotype in one of the backcrosses, we demonstrated that it is possible in some instances to select promising candidate genes based on known genetic interactions and bioinformatics based searches. The utility of this method was subsequently demonstrated by the identification of functional polymorphisms in both genes of interest, and by the in vivo replication of the latency phenotype in a transgenic experiment. We are currently pursuing this and other strategies to attempt to identify likely candidates for the metastasis efficiency genes, starting with the locus on chromosome 19. Finally, we plan to take advantage of the unique resources of mouse genetics to develop an integrated "trans-ome", genome, transcriptome and proteome, characterization of mammary tumor metastasis. By exploring the expression patterns and protein levels and post-translational modification in the AKXD recombinant inbred mouse-mapping panel used for genetic mapping of the metastasis modifier genes, we should be able to explore the interface of genetic susceptibility to tumor dissemination with the intricate and interwoven biochemical pathways of the cell. We believe that this global approach to interrogating the metastatic process may yield novel insights into the complex and multiple pathways involved in this process, and potentially lead to exciting new strategies and targets for clinical intervention.

肿瘤扩散或转移的过程是癌症临床管理的重要方面。在大多数情况下，肿瘤局限性的癌症患者比那些扩散性肿瘤的患者有更好的预后。大多数癌症死亡率与转移性疾病有关，而不是原发性肿瘤。据估计，60-70%的患者在诊断时已经进展为转移性疾病，因此更好地理解导致肿瘤扩散的因素至关重要。已经进行了大量的研究来阐明这一过程的各个组成部分。因此，人们对与转移进展相关的不同分子和途径了解很多，包括癌基因的激活、金属蛋白酶的募集和运动因子。转移相关的杂合性丢失也被用作鉴定称为转移抑制因子的一类基因成员的工具。迄今为止，已经描述了这类基因的八个成员：NM 23、KISS 1、KAI 1、E-钙粘蛋白、MKK 4、TIMPs、Maspin、BRMS 1、RhoGDI 2。 尽管有这些丰富的信息，但肿瘤传播的关键起始事件或分子途径仍不清楚。解开转移的复杂性的困难的一部分可能是由于与恶性潜能相关的多个会聚途径。另一个混杂因素可能是肿瘤扩散效率的遗传调节。确定转移过程的关键调控成分将起到两个作用。首先，它们可能提供比当前标准更准确的患者潜在转移进展的预后标志物。其次，它们可以提供对肿瘤传播中关键事件的见解，可能导致额外的研究途径或新疗法的开发。 我的实验室使用动物模型进行基因发现和/或测试假设，这些假设在人群中很难或不可能做到，包括流行病学相关性的直接实验测试。我实验室的重点是结合遗传学和基因组学方法，以确定体质遗传组成如何影响恶性进展的易感性。研究的模型是高度侵袭性、转移性转基因乳腺肿瘤FVB/N-TgN（MMTV-PyVT）634 Mul小鼠，其在100日龄时约85%的动物中出现肺转移性病变。通过进行基于育种的菌株调查，我的实验室证明了宿主的遗传背景是转移潜力的主要决定因素的第一个体内证据。使用数量性状遗传分析的回交或重组近交系小鼠种群，我们随后映射的位置，至少有两个显着的修饰基因，并确定了其他三个暗示修饰基因。 目前，我的实验室正在应用传统的小鼠遗传和基于群体的策略，试图识别和表征在不同基因型中观察到的转移效率的基因，途径和多态性。目前正在采取双管齐下的战略。该策略的第一臂是基于常规的方法，即开发间隔特异性同源和亚同源动物，以生成修饰基因的高分辨率映射，然后是标准的位置候选策略。 虽然传统策略成功的可能性很高，但这是一个缓慢而费力的过程，需要大量的动物育种和操作。因此，在与传统的同类基因为基础的战略，我们正在探索替代策略的候选基因选择修饰。例如，在一个回交中使用潜伏期作为表型，我们证明了在某些情况下可以基于已知的遗传相互作用和基于生物信息学的搜索来选择有希望的候选基因。该方法的实用性随后被证明在两个感兴趣的基因的功能多态性的鉴定，并在转基因实验中的潜伏表型的体内复制。我们目前正在寻求这种和其他策略，试图确定转移效率基因的可能候选人，从19号染色体上的基因座开始。 最后，我们计划利用小鼠遗传学的独特资源，开发一个整合的“trans-ome”，基因组，转录组和蛋白质组，表征乳腺肿瘤转移。通过探索用于转移修饰基因遗传图谱的AKXD重组近交系小鼠图谱组中的表达模式、蛋白水平和翻译后修饰，我们应该能够探索肿瘤播散的遗传易感性与细胞复杂交织的生化途径的界面。我们相信，这种询问转移过程的全球方法可能会对该过程中涉及的复杂和多途径产生新的见解，并可能导致令人兴奋的新策略和临床干预靶点。