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

• 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
• 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

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.

项目摘要 肝细胞癌（HCC）是一种致命的实体瘤，高度依赖于新血的募集 血管，没有共同的基因组靶点。对于大多数实体瘤，转移引起不成比例的 发病率和死亡率。LIN 28 B-一种在肿瘤和发育中表达的RNA结合蛋白 LIN 28 B在HCC中的表达升高与HCC中LIN 28 B表达的增加相关。 死亡的危险。我们最近发现LIN 28 B是胰腺癌转移的一种新驱动因素，并提出在胰腺癌转移中， 目的1通过一系列完整的分子、细胞和动物实验， 由LIN 28 B驱动。在目标2中，我建议在体外将稳健的共培养物（HCC细胞和内皮细胞）偶联， 体内模型，以确定肝癌细胞中LIN 28 B表达如何调节其对内皮细胞的作用， 进而刺激肝癌转移表型。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， 常规和新型组织染色的纯化/分析技术和计算分析 技术来表征LIN 28 B的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。总的来说，这项工作将提供功能原理 用于开发靶向LIN 28 B通路和相关血管调节通路的新疗法， HCC和开发新的匹配生物标志物。申请人Joseph Franses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， 25%的人在临床实践中照顾癌症患者。他提出了一个五年职业发展计划， 实现他成为翻译研究独立研究者的目标。Franses博士召集了一个 国际公认的专家咨询委员会，提供科学和职业指导。他 与癌症基因组学、分子生物学、肿瘤动物模型方面的专家建立了合作关系， 计算生物学提供实验建议和该领域的具体培训。弗兰西斯博士将进行 这项研究和利用特殊的研究和教学环境在芝加哥大学 癌症中心芝加哥大学拥有杰出的研究群体， 成功指导独立医生-科学家的记录。这将是一个理想的环境 成功完成这些实验，实现了Franses博士的职业目标， 致力于改善胃肠道癌症患者的护理的独立医生-科学家。