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

定义 LIN28B 在肝细胞癌中的促转移和内皮调节作用

基本信息

批准号：
10865508
负责人：
Joseph Wang Franses
金额：
$ 26.53万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10865508
关键词：
Advisory Committees Affect Agar Angiogenic Factor Animal Experiments Animal Model Animals Automobile Driving Behavior Biological Assay Biological Markers Biological Models Biology Blood Vessels Cancer Center Cell Communication Cell Density Cell Line Cell model Cells Chicago Clinical Clinical Data Coculture Techniques Collaborations Communities Computational Biology Computer Analysis Consensus DNA Sequence Alteration Data Set Dedications Development Development Plans Dissociation Drug Targeting Educational process of instructing Endothelial Cells Endothelium Environment Genes Genomics Goals Hep3B Hepatic Heterogeneity Human In Vitro International Invaded Investigation Knock-out Link Maintenance Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of pancreas Mentorship Metastatic Carcinoma Modeling Molecular Molecular Biology Morbidity - disease rate Neoplasm Circulating Cells Neoplasm Metastasis Oncologist Outcome PECAM1 gene Pathway interactions Patient Care Patients Phenotype Physicians Primary Neoplasm Primary carcinoma of the liver cells Prognosis Proliferating RNA Binding RNA immunoprecipitation sequencing RNA-Binding Proteins Recurrence Regulatory Pathway Research Research Personnel Role Scientist Series Solid Neoplasm Specimen Stains Tail Technology Time Tissue Stains Tissues Training Translational Research Tube Tumor Tissue Universities Veins Work biomarker development cancer cell cancer genomics career career development clinical practice drug development experience experimental study fitness gain of function implantation improved in vitro Assay in vivo Model migration mortality mortality risk nano-string new therapeutic target novel oncofetal antigen overexpression paracrine pharmacologic pluripotency preimplantation recruit single-cell RNA sequencing spatial relationship tool transcriptome sequencing transcriptomics tumor tumor microenvironment

项目摘要

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.

项目概要肝细胞癌 (HCC) 是一种致命的实体瘤，高度依赖新血的补充对于大多数实体瘤来说，转移会导致不成比例的肿瘤。 LIN28B——一种在肿瘤和发育中表达的RNA结合蛋白。组织——对于 HCC 的发展至关重要，HCC 中 LIN28B 表达升高与我们最近发现 LIN28B 是胰腺癌转移的新驱动因素，并提出目标 1 使用一系列综合的分子、细胞和动物实验来确定 HCC 是否转移由 LIN28B 驱动在目标 2 中，我建议在体外结合稳健的共培养（HCC 细胞和内皮细胞）。体内模型来定义 HCC 细胞中的 LIN28B 表达如何调节其对内皮细胞的影响，这在在目标 3 中，我将利用我们在新型循环肿瘤细胞方面的专业知识。传统和新型组织染色的纯化/分析技术和计算分析使用初级技术来表征 LIN28B 的转移驱动和内皮调节作用的技术总的来说，这项工作将为人类循环肿瘤细胞和肿瘤组织标本提供功能原理。开发针对 LIN28B 通路和相关血管调节通路的新疗法 HCC 和新型匹配生物标志物的开发申请人 Joseph Franses 博士是一位肿瘤学家。他将花费 75% 的时间在芝加哥大学癌症中心进行转化研究和 25% 从事癌症患者的临床实践他制定了一个五年职业发展计划为了实现成为转化研究独立研究者的目标，弗朗西斯博士组建了一份报告。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。与癌症基因组学、分子生物学、肿瘤动物模型等领域的专家建立了合作 Franses 博士将在计算生物学领域提供实验建议和具体培训。这项研究并利用芝加哥大学卓越的研究和教学环境芝加哥大学癌症中心拥有杰出的研究团体，并且有着悠久的历史。独立医师科学家的成功指导记录这将是一个理想的环境。成功完成这些实验并实现了 Franses 博士成为一名独立医师科学家致力于改善胃肠道癌症患者的护理。