Molecular Drivers of Elevated Gallbladder Cancer Incidence in New Mexico

项目总结： 胆囊癌(GBC)是胃肠道第五大常见恶性肿瘤，也是 人类的胆汁树。美国约有4,000-5,000例新确诊的胆囊癌病例 每年一次。生存结果令人沮丧，5年存活率只有8%左右，使其成为最致命的之一 癌症。GBC具有明显的地理发病模式，具有全球热点。这些热点包括 智利、玻利维亚、印度和美国新墨西哥州等国。GBC发病率为 少数族裔占多数的美洲原住民(高出5-8倍)和拉美裔(高出2-4倍)的比例异常高 与居住在新墨西哥州的高加索人相比)。年GBC发病率差异的原因 NM是未知的，在我们对胆囊癌发生的理解上存在着严重的差距。 我们推测环境中的重金属暴露是造成GBC差异的关键风险因素 在新墨西哥州的少数民族中可见。美国西南部(新墨西哥州、亚利桑那州、德克萨斯州和北卡罗来纳州)有着悠久的环境 废弃的重金属矿留下的遗产。这些地雷通常位于一个重要的矿场附近。 新墨西哥州处于社会经济不利地位的美国原住民和西班牙裔社区的数量。为了证明我们的 GBC假说，我们建议使用新的墨西哥患者来源的胆囊腺上皮细胞系 求婚。目标1将使用手术后的胆囊样本来确定体细胞突变情况和 GBC的关键分子驱动因素以种族和性别依赖的方式。目标2将确定 新墨西哥州两种重要金属铀和镉对GB磷酸蛋白质组的暴露 细胞信号失控。特别是，我们将重点关注金属暴露驱动的PI3K-Akt和 MAPK信号通路改变。目标3将确定镉和铀暴露对 胆囊壁上皮屏障破坏和伤口愈合是胆囊癌差异的机制解释 在新墨西哥州看到的。目标3将首次证实金属诱导的GB上皮屏障破坏的作用 引起慢性跨壁炎症，这是众所周知的胆囊癌发生的先决条件。 我们的长期目标是了解胆囊癌发生的分子机制。 创新的、高通量的生物信息学方法。这一基础科学建议深刻地告知 我们实验室目前正在进行转译临床倡议。最后，这项提议还将提供一个坚定的 实现预防性、基于人群的筛查措施以缓解GBC差异的科学依据 在新墨西哥州的美洲原住民和西班牙裔社区。

Project Summary: Gallbladder Cancer (GBC) is the fifth most common malignancy of the GI tract and the most common in the human biliary tree. Approximately 4,000-5,000 new cases of GBC are diagnosed in the United States annually. Survival outcomes are dismal with only ~8% 5-year survival rate, making it one of the deadliest cancers. GBC has a distinct geographical incidence pattern with global hotspots. These hotspots include countries like Chile, Bolivia, India and the state of New Mexico (NM) in the United States. GBC incidence is abnormally high among the “minority-majority” Native Americans (5-8 fold higher) and Hispanics (2-4 fold higher) compared to Caucasians living in New Mexico. The reasons underlying GBC incidence disparities in NM is unknown and there are critical gaps in our understanding of gallbladder carcinogenesis. We postulate environmental heavy metal exposure is the key risk factor responsible for GBC disparities seen among minorities of NM. The southwestern United States (NM, AZ, UT and NV) has a long environmental legacy of abandoned heavy metal mines. These mines are usually found in close proximity to a significant number of socio-economically disadvantaged Native American and Hispanic communities of NM. To prove our GBC hypothesis, we propose the use of New Mexican patient derived gallbladder epithelial cell lines in this proposal. Aim 1 will use post-surgical gallbladder samples to determine the somatic mutational landscapes and key molecular drivers of GBC in an ethnicity and gender dependent manner. Aim 2 will determine the impact of exposures of two metals of significance in New Mexico, uranium and cadmium, on the GB phosphoproteomic cell signaling dysregulation. In particular, we will focus on the role of metal exposure driven PI3K-Akt and MAPK signaling pathway alterations. Aim 3 will determine the effects of cadmium and uranium exposure on gallbladder epithelial barrier disruption and wound healing as a mechanistic explanation of GBC disparities seen in NM. Aim 3 will confirm, for the first time, the role of metal induced disruption of the GB epithelial barrier causing chronic transmural inflammation which is a well-known prerequisite of gallbladder carcinogenesis. Our long-term goal is to understand the molecular mechanisms of gallbladder carcinogenesis using innovative, high-throughput bioinformatics approaches. This basic science proposal deeply informs the translational clinical initiatives currently underway in our lab. Finally, this proposal will also provide a firm scientific basis to enable preventative, population based screening measures to alleviate GBC disparities seen in Native American and Hispanic communities of New Mexico.