Genetic Modifiers of Intitiation and Progression of Mamm

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。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。所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日龄时在85%的动物中发生肺转移性病变。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。利用回交或重组近交系小鼠群体的数量性状遗传分析，我们随后绘制了小鼠基因组中一些修饰基因的位置。最近，我的实验室一直在使用一种我们称之为“transomics”的策略来开始鉴定负责调节转移效率的基因。使用单倍型作图，基因表达谱分析，蛋白质组学，功能基因组学，序列分析和基因敲除技术的组合，我们已经确定了一些有趣的候选基因。这种方法导致了最近对第一个转移效率修饰基因Sipa 1的表征。通过改变该分子的酶促效率的点突变或通过调节肿瘤细胞内该蛋白质的相对量来调节该基因的功能，显示出对肺的转移性定殖具有显著影响。据我们所知，这是多态性影响转移进展的第一个直接例子。我们与UCI的Anton-Culver博士合作，目前正在进行初步的人类流行病学研究，以确定SIPA 1多态性是否也可能在人类乳腺癌转移的效率中发挥作用。此外，我的实验室一直在使用我们的遗传和transomic资源来解决转移研究界出现的一个悖论。

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. 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 a number of modifier genes in the mouse genome.More recently, my laboratory has been using a strategy we call "transomics" to begin to identify the genes that are responsible for the modulation of metastatic efficiency. Using a combination of haplotype mapping, gene expression profiling, proteomics, functional genomics, sequence analysis, and gene knock-down technologies we have been characterizing a number of interesting candidate genes. This approach has led to the recent characterization of the first of the metastasis efficiency modifier genes, Sipa1. Modulation of the function of this gene, either by a point mutation that alters the enzymatic efficiency of this molecule, or by modulating the relative amounts of this protein within the tumor cell, was shown to have significant impact on metastatic colonization of the lung. This was, to the best of our knowledge, the first direct example of a polymorphism influencing metastatic progression. In collaboration with Dr. Anton-Culver at UCI, we are currently performing preliminary human epidemiology studies to determine whether SIPA1 polymorphisms may also play a role in the efficiency of human breast cancer metastasis.In addition, my laboratory has been using our genetic and transomic resources to address a paradox that has arisen in the metastasis research community.