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ARF6 function in cancers driven by RAS hyperactivation

ARF6 在 RAS 过度激活驱动的癌症中发挥作用

基本信息

批准号：
10675597
负责人：
Jae Hyuk Yoo
金额：
$ 24.76万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-03 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10675597
关键词：
ADP-ribosylation factor 6 Affect Binding Biochemical Biological Assay Cancer Biology Catalytic Domain Cell Nucleus Cell Proliferation Cell membrane Cells Clinic Cutaneous Melanoma Cytoplasmic Vesicles Data Development Ectopic Expression Foundations Future Genetic Transcription Genetically Engineered Mouse Glioblastoma Glioma Goals Growth Guanosine Triphosphate Phosphohydrolases Human Immune system Immunocompetent Immunocompromised Host In Vitro Individual Knock-out Knowledge Lipids Location Longevity MAP Kinase Gene MAPK Signaling Pathway Pathway Malignant Neoplasms Measures Mediating Membrane Methods Modification Monomeric GTP-Binding Proteins Mus Mutation N-Cadherin NF1 gene Neoplasm Metastasis Neurofibromatosis 1 Neurofibrosarcoma Oncogenes Oncogenic PIK3CG gene Pathway interactions Pharmaceutical Preparations Phase Play Proliferating Proteins RAS driven cancer RAS inhibition Receptor Protein-Tyrosine Kinases Recombinants Regulator Genes Research Risk Role Signal Pathway Signal Transduction Testing Therapeutic Tissues Training Tumor Suppressor Genes Tumor-Derived Uveal Melanoma WNT5A gene Xenograft Model Xenograft procedure beta catenin cancer cell cancer therapy developmental disease evidence base farnesylation human model in vivo in vivo Model insight interdisciplinary approach knock-down leukemia melanoma mouse model myristoylation neoplastic cell palmitoylation pharmacologic postnatal programs sarcoma small molecule inhibitor therapeutically effective trafficking tumor tumor growth tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Activating mutations in RAS or mutations in RAS regulatory genes that lead to hyperactivated RAS are drivers of human cancer. Neurofibromatosis type 1 (NF1) is a developmental disease caused by loss of the NF1 tumor suppressor gene, which encodes neurofibromin, a large protein that inactivates RAS through its GTPase activating function. Loss of NF1 leads to the hyperactivation of RAS and increases the risk of developing multiple cancers, including malignant peripheral nerve sheath tumors (MPNSTs). RAS activation promotes signaling of several downstream pathways that drive oncogenesis, including the PI3K and MAPK signaling pathways. Although many attempts have been made to target RAS either directly or indirectly, none of them have yet been successful in the clinic and therefore new insights into the precise mechanisms that govern RAS signaling are needed. The small GTPase protein ARF6 has been implicated in the growth and metastasis of many cancers. In uveal and cutaneous melanomas, ARF6 promotes the trafficking of oncogenic Gq or -catenin to appropriate intracellular locations where signaling or transcription is enhanced. Our preliminary data suggest that ARF6 may also be regulating RAS signaling in NF1-deficient MPNSTs by controlling RAS intracellular trafficking and that ARF6 controls proliferation of NF1-deficient tumor cells. Activated ARF6 appears to be necessary for RAS lipid modifications, such as palmitoylation and farnesylation, which are essential for RAS membrane localization and for binding with its effectors, RAF and p110 (a PI3K catalytic subunit). Based on these preliminary data, we hypothesize that ARF6 promotes tumorigenesis in NF1-deficient tissues by controlling RAS trafficking and signaling. We will test this hypothesis by pursuing the following aims. In Aim 1, we will determine whether loss of NF1 activates ARF6 to control tumor cell proliferation by regulating RAS subcellular localization and signaling. These studies will involve multidisciplinary approaches to determine how NF1 regulates ARF6 and how ARF6 controls cell proliferation, RAS lipid modifications, intracellular localization, and signaling. In Aim 2, we will assess ARF6 function in tumor growth in an orthotopic xenograft mouse model of NF1-deficient human MPNST. These studies will allow us to determine how ARF6 knockdown or pharmacologic inhibition affects in vivo growth of tumors derived from human cancer cells in an immunocompromised mouse model. In Aim 3, we will determine whether ARF6 is necessary for tumor formation and growth in a genetically engineered mouse model of NF1- deficient cancers. These studies will involve either knocking out Arf6 or pharmacologically inhibiting ARF6 in immunocompetent Nf1+/-; Trp53+/- mice to determine the in vivo role of ARF6 in NF1-deficient tumorigenesis in the presence of a competent immune system. This proposal will provide essential training in multidisciplinary approaches and expand the candidate’s knowledge of cancer biology (K99 phase) and will establish the foundations for an independent research program focused on the roles of ARF6 in cancers driven by not only NF1 deficiency but also hyperactivated RAS (R00 phase).

项目总结/摘要 RAS激活突变或RAS调节基因突变导致RAS过度激活是驱动因素人类癌症1型神经纤维瘤病（NF 1）是一种由NF 1肿瘤丢失引起的发育性疾病一种抑制基因，编码神经纤维蛋白，一种通过其GT3使RAS失活的大蛋白激活功能。NF 1的缺失导致RAS的过度激活，并增加发生多发性硬化的风险。癌症，包括恶性外周神经鞘瘤（MPNST）。RAS激活促进几个下游途径驱动肿瘤发生，包括PI 3 K和MAPK信号通路。尽管已经做出了许多直接或间接针对RAS的尝试，但还没有一个成功。在临床上取得了成功，因此对控制RAS信号传导的精确机制有了新的认识， needed.小GT3蛋白ARF 6与许多癌症的生长和转移有关。在葡萄膜和皮肤黑色素瘤中，ARF 6促进致癌G-β q或β-连环蛋白运输到适当的细胞，信号传导或转录增强的细胞内位置。我们的初步数据表明，ARF 6可能也可以通过控制RAS细胞内运输来调节NF 1缺陷型MPNST中的RAS信号传导， ARF 6控制NF 1缺陷肿瘤细胞的增殖。活化的ARF 6似乎是RAS脂质修饰，如棕榈酰化和法尼基化，这是RAS膜定位所必需的，用于与其效应物RAF和p110（PI 3 K催化亚基）结合。根据这些初步数据，我们假设ARF 6通过控制RAS运输促进NF 1缺陷组织中的肿瘤发生，发信号。我们将通过追求以下目标来检验这一假设。在目标1中，我们将确定损失是否 NF 1通过调节RAS的亚细胞定位和信号传导激活ARF 6来控制肿瘤细胞增殖。这些研究将涉及多学科的方法，以确定NF 1如何调节ARF 6，以及ARF 6如何调节ARF 6。控制细胞增殖、RAS脂质修饰、细胞内定位和信号传导。在目标2中，我们将评估 ARF 6在NF 1缺陷型人MPNST原位异种移植小鼠模型中肿瘤生长中的功能。这些研究将使我们能够确定ARF 6敲低或药理学抑制如何影响体内生长，来源于人癌细胞的肿瘤。在目标3中，我们将确定在NF 1基因工程小鼠模型中，ARF 6是否是肿瘤形成和生长所必需的？缺陷型癌症这些研究将涉及敲除Arf 6或抑制Arf 6。免疫活性Nf 1 +/-; Trp 53 +/-小鼠，以确定ARF 6在NF 1缺陷型肿瘤发生中的体内作用。免疫系统的存在。这项建议将提供多学科的基本培训，方法和扩大候选人的癌症生物学知识（K99阶段），并将建立一个独立研究项目的基础，重点关注ARF 6在癌症中的作用，这不仅是因为 NF 1缺乏，但也过度激活RAS（R 00期）。