Defining pro-metastatic and endothelial-regulatory roles for LIN28B in hepatocellular carcinoma

项目总结 肝细胞癌是一种致命的实体瘤，高度依赖新血的补充。 血管，没有共同的基因组靶点。对于大多数实体肿瘤来说，转移导致不成比例的 发病率和死亡率的程度。Lin28b--一种在肿瘤和发育中表达的RNA结合蛋白 组织--对肝细胞癌的发展是必不可少的，而肝细胞癌中Lin28b的高表达与 有死亡的危险。我们最近发现Lin28b是胰腺癌转移的新驱动因素，并在 目的1利用一系列分子、细胞和动物实验来确定肝细胞癌是否转移。 由LIN28B驱动。在目标2中，我建议将强大的体外共培养(肝癌细胞和内皮细胞)与 体内模型以确定Lin28b在肝癌细胞中的表达如何调节其对内皮细胞的影响，这在 进而刺激肝细胞癌转移表型。在目标3中，我将利用我们在新型循环肿瘤细胞方面的专业知识 常规组织染色和新型组织染色的纯化/分析技术及计算分析 应用原代技术研究Lin28b的肿瘤转移驱动和内皮调节作用 人循环肿瘤细胞和肿瘤组织标本。总体而言，这项工作将提供功能基础 针对Lin28b通路和相关的血管调节通路的新疗法的开发 并用于开发新的匹配生物标记物。申请者约瑟夫·弗兰西斯博士是一名肿瘤学家。 在芝加哥大学癌症中心。他将花费75%的时间进行翻译研究和 25%的人在临床实践中照顾癌症患者。他概述了一项五年职业发展计划，以 达到他成为翻译研究的独立调查员的目标。弗朗西斯博士已经组装了一个 由国际公认的专家组成的咨询委员会提供科学和职业指导。他有 与癌症基因组学、分子生物学、肿瘤动物模型和 计算生物学，提供实验建议和该领域的具体培训。弗朗西斯博士将进行 这项研究和利用芝加哥大学卓越的研究和教学环境 癌症中心。芝加哥大学拥有一个杰出的研究团体，并有很长的发展道路 成功指导独立内科医生-科学家的记录。这将是一个理想的环境， 这些实验的成功完成和弗兰西斯博士成为一名 独立内科医生-科学家，致力于改善胃肠道癌症患者的护理。

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is a lethal solid tumor that is highly dependent on recruitment of new blood vessels and has no common genomic targets. As for most solid tumors, metastasis causes a disproportionate degree of morbidity and mortality. LIN28B – an RNA-binding protein expressed in tumors and in developing tissues – is essential for HCC development and elevated LIN28B expression in HCC correlates with an increased risk of death. We recently identified LIN28B as a novel driver of pancreatic cancer metastasis and propose in Aim 1 to use an integrated series of molecular, cellular, and animal experiments to determine if HCC metastasis is driven by LIN28B. In Aim 2, I propose to couple robust co-culture (HCC cell and endothelial cell) in vitro and in vivo models to define how LIN28B expression in HCC cells modulates its effect on endothelial cells, which in turn stimulate the HCC metastatic phenotype. In Aim 3, I will utilize our expertise in novel circulating tumor cell purification/analysis technologies and computational analysis of conventional and novel tissue staining technologies to characterize the metastasis-driving and endothelial regulatory roles of LIN28B using primary human circulating tumor cell and tumor tissue specimens. Collectively, this work will provide functional rationale for the development of new therapies targeting the LIN28B pathway and linked vascular-regulatory pathways in HCC and for the development of novel matched biomarkers. The applicant, Dr. Joseph Franses, is an oncologist at the University of Chicago Cancer Center. He will spend 75% of his time performing translational research and 25% in clinical practice caring for patients with cancer. He has outlined a five-year career development plan to meet his goal of becoming an independent investigator in translational research. Dr. Franses has assembled an Advisory Committee of internationally recognized experts to provide scientific and career mentorship. He has established collaborations with experts in cancer genomics, molecular biology, tumor animal modeling, and computational biology to provide experimental advice and specific training in the field. Dr. Franses will conduct this research and leverage the exceptional research and teaching environment at the University of Chicago Cancer Center. The University of Chicago harbors an outstanding research community and has a long track record for successful mentorship of independent physician-scientists. This will be an ideal environment for successful completion of these experiments and the realization of Dr. Franses’ career goal of becoming an independent physician-scientist dedicated to improving the care of patients with gastrointestinal cancers.