The Role of the Small GTPase ARF6 in Oncogenic Signaling and Tumorigenesis

小 GTP 酶 ARF6 在致癌信号传导和肿瘤发生中的作用

• 批准号: 8967336
• 负责人: Allie H. Grossmann
• 金额: $ 18.04万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-06 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967336
• 关键词: ADP-ribosylation factor 6; Adherens Junction; Adhesions; Advisory Committees; Anatomy; Arrestins; BRAF gene; Biological Assay; Biology; Bone Tissue; Cadherins; Cancer Biology; Clinical; Committee Members; DNA; Data; Databases; Development; Disease Progression; Doctor of Philosophy; Educational Intervention; Ensure; Environment; Etiology; FZD4 gene; Family; Foundations; Funding; Future; Genetic; Genetic Transcription; Genetically Engineered Mouse; Goals; Grant; Growth; Guanine; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; H-Cadherin; Health; Health Sciences; Housing; Human; Human Genetics; Huntsman Cancer Institute at the University of Utah; In Vitro; Incidence; Institutes; Internal Medicine; Intervention; Investigation; Knowledge; Laboratories; Laboratory Personnel; Lead; Learning; Link; MAP Kinase Gene; Maintenance; Malignant Neoplasms; Maps; Mediating; Medicine; Mentors; Mismatch Repair; Molecular; Monomeric GTP-Binding Proteins; Mus; N-Cadherin; National Cancer Institute; Neoplasm Metastasis; Neurobiology; Newly Diagnosed; Oncogenic; Operative Surgical Procedures; Oregon; PI3K/AKT; Pathology; Pathway interactions; Patients; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physicians; Play; Protein Tyrosine Kinase; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Reagent; Recording of previous events; Recruitment Activity; Research; Research Personnel; Risk; Role; Scaffolding Protein; Science; Scientist; Secure; Serine; Services; Signal Pathway; Signal Transduction; Site; Subcutaneous Injections; Substrate Specificity; Surgical Pathology; System; Techniques; Testing; Threonine; Time; Transactivation; Tyrosine; Tyrosine Phosphorylation; United States; Universities; Update; Utah; Virus; WNT Signaling Pathway; WNT5A gene; Woman; Work; Writing; adapter protein; beta catenin; cancer genomics; career; clinical practice; design; experience; graduate student; improved; in vivo; in vivo Model; instructor; melanocyte; melanoma; member; men; molecular oncology; mouse model; new therapeutic target; next generation; novel; oncology; professor; receptor; recombinase; soft tissue; targeted cancer therapy; therapeutic target; tumor; tumor initiation; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): Candidate: I, Allie H. Grossmann, MD PhD, am an Instructor in the Department of Pathology, Division of Anatomic Pathology and Oncology, at the University of Utah. My clinical practice includes Molecular Oncology and the Bone & Soft Tissue subspecialty service in Surgical Pathology (combined 20% full time professional effort). My primary professional effort is focused on research (75%) into the biology of cancer metastasis. We recently published our findings on this topic, titled "The small GTPase ARF6 stimulates β- catenin transcriptional activity during WNT5A-mediated melanoma invasion and metastasis"1. This work provides the foundation for my current research, as outlined in this proposal, which is funded by the Department of Pathology. My mentors include Sheri Holmen, PhD and Dean Y. Li, MD PhD. My prior research experiences were at Oregon Health & Science University where I was a research assistant for R. Michael Liskay, PhD, studying DNA Mismatch Repair, and a graduate student with Brian J. Druker, MD, studying catalytic substrate specificity of protein tyrosine kinases. My immediate career goals over the next 5 years include learning and implementing techniques for creating conditional genetic mouse models, updating and broadening my knowledge of cancer biology, metastasis, and cancer genomics, becoming proficient in grant writing, accomplishing the AIMS outlined in this proposal, publishing the results, securing grants, expanding my laboratory personnel, generating RO1 applications, and establishing excellence in my clinical practice. My long term career goals include building an enterprise of investigations into the discovery of therapeutic targets for treating cancer metastasis, developing clinical molecular tests that identify patients at risk for disease progression, and clinical molecular assays that identify actionable targets for intervention, and training the next generation of physicians and scientists. Environment: My mentors include Sheri L. Holmen, PhD, Associate Professor in the Department of Surgery and investigator at the Huntsman Cancer Institute (HCI) at the University of Utah, and Dean Y. Li, MD PhD, Professor of Medicine, Human Genetics, and Oncologic Sciences at the University of Utah. Dr. Holmen provides me with laboratory space and expertise in genetically engineered mouse models of melanoma and cancer signaling, including WNT/-catenin. Dr. Li provides expertise in ARF6 related signaling, access to unique ARF6 pathway reagents, and wisdom in blending the dual roles of a physician scientist. My advisory committee consists of Jan Christian, PhD (Professor of Neurobiology & Anatomy and Internal Medicine), Charles Murtaugh, PhD (Associate Professor of Human Genetics), Richard Dorsky, PhD (Associate Professor of Neurobiology and Anatomy), Matthew VanBrocklin, PhD (Assistant Professor of Surgery), and Rodney Stewart, PhD (Assistant Professor of Oncologic Sciences). Together these investigators provide expertise in developmental & cancer signaling and biology, various in vivo models, and melanocyte and melanoma-specific biology. My department chair, Peter Jensen, MD, as well as other clinical colleagues and mentors in the Department of Pathology, are fully supportive of my research endeavors and strive to ensure that I have clinical guidance as needed and guaranteed protected time for research. I have laboratory space in the Holmen Lab, in the Huntsman Cancer Institute, which houses investigators from multiple departments and where some of my clinical activities occur. The HCI is in close proximity to the Eccles Institute of Human Genetics, where Dr. Li's laboratory resides, and other research buildings that house my advisory committee members. Research: Delineation of pathways controlling cancer progression is paramount to the discovery of new targets and progress in improving cancer survival. Recently we uncovered a novel signaling pathway whereby the small GTPase ADP Ribosylation Factor 6 (ARF6) is activated by WNT5A/Frizzled4 to release -catenin from N-cadherin, facilitating a switch in -catenin function from adhesion to transcription and promotin invasion and metastasis of melanoma1. The goal of this study is to determine howARF6 orchestrates and links multiple cancer signaling pathways. [New progress on this project has revealed potential mechanisms downstream of ARF6 activation that link PI3K/AKT signaling to -catenin activation. Furthermore, we have established a relationship between ARF6 and known drivers of melanoma in vivo; oncogenic BRAF and the PI3K/AKT pathway]. AIMS 1 and 2 focus on determining how WNT activates ARF6 and how this activation leads to release of transcriptionally active -catenin from cadherin. AIM3 is designed to test the role of ARF6 in melanoma formation and metastasis in established genetic mouse models that recapitulate the molecular etiology of melanoma in humans. These studies will help identify molecular mechanisms that control melanoma growth and metastasis, delineate a role for ARF6 in established oncogenic pathways (WNT/ -catenin, BRAF/MAPK, and PI3K/AKT), and reveal that the small GTPase ARF6 is the link that connects these infamous pathways.

 描述(由申请人提供)：应聘者：我，艾莉·H·格罗斯曼，医学博士，犹他大学解剖病理学和肿瘤学分部病理学系讲师。我的临床实践包括分子肿瘤学和外科病理学的骨与软组织专科服务(加起来有20%的全职专业工作)。我的主要职业努力集中在癌症转移生物学的研究上(75%)。我们最近发表了我们在这个主题上的发现，题为“在WNT5A介导的黑色素瘤侵袭和转移过程中，小GTP酶ARF6刺激β-连环蛋白转录活性”1。这项工作为我目前的研究提供了基础，正如这项由病理学系资助的提案中概述的那样。我的导师包括谢莉·霍尔曼博士和李彦宏院长，他是医学博士。我之前的研究经验是在俄勒冈健康与科学大学，在那里我是R.Michael Liskay博士的研究助理，研究DNA错配修复，并与Brian J.Druker医学博士一起攻读研究生，研究蛋白质酪氨酸激酶的催化底物特异性。在接下来的5年里，我的直接职业目标包括学习和实施创建条件遗传小鼠模型的技术，更新和拓宽我对癌症生物学、转移和癌症基因组学的知识，精通拨款申请，实现本提案中概述的目标，发布结果，获得拨款，扩大我的实验室人员，生成RO1应用程序，并在我的临床实践中建立卓越的地位。我的长期职业目标包括建立一个企业，研究发现治疗癌症转移的治疗靶点，开发临床分子测试来识别有疾病进展风险的患者，以及临床分子分析来确定可操作的干预目标，以及培训下一代医生和科学家。环境：我的导师包括犹他州大学亨斯迈癌症研究所(HCI)外科副教授兼研究员Sheri L.Holman博士，以及犹他州大学医学、人类遗传学和肿瘤学教授、医学博士Dean Y.Li。霍尔曼博士为我提供了黑色素瘤和癌症信号基因工程小鼠模型的实验室空间和专业知识，包括wnt/-catenin。李博士在ARF6相关信号转导方面提供专业知识，获得独特的ARF6途径试剂，并在融合内科科学家的双重角色方面提供智慧。我的咨询委员会成员包括简·克里斯蒂安(神经生物学、解剖学和内科教授)、查尔斯·穆尔陶(人类遗传学副教授)、理查德·多尔斯基(神经生物学和解剖学副教授)、马修·范布罗克林(外科助理教授)和罗德尼·斯图尔特(肿瘤学助理教授)。这些研究人员共同提供发育和癌症信号和生物学、各种体内模型以及黑素细胞和黑色素瘤特异性生物学方面的专业知识。我的科室主任、医学博士Peter Jensen以及病理学部门的其他临床同事和导师都全力支持我的研究工作，并努力确保我在必要时获得临床指导，并保证研究时间受到保护。我在亨茨曼癌症研究所的霍尔门实验室有实验室空间，那里有来自多个部门的研究人员，我的一些临床活动就是在这里进行的。人机界面靠近李博士的实验室所在的埃克尔斯人类遗传学研究所，以及我的顾问委员会成员所在的其他研究大楼。研究：描绘控制癌症进展的途径对于发现新的靶点和提高癌症存活率至关重要。最近，我们发现了一条新的信号通路，通过WNT5A/Frizzled4激活小GTP酶ADP核糖化因子6，从N-钙粘连蛋白中释放-连环蛋白，促进-连环蛋白功能从黏附到转录的转换，促进黑色素瘤的侵袭和转移。这项研究的目标是确定ARF6如何协调和连接多个癌症信号通路。[该项目的新进展揭示了ARF6激活下游的潜在机制，该机制将PI3K/AKT信号与-连环蛋白激活联系起来。此外，我们已经建立了ARF6与体内已知的黑色素瘤驱动因素的关系；致癌的BRAF和PI3K/AKT途径]。目标1和2的重点是确定WNT如何激活ARF6，以及这种激活如何导致转录活性的-连环蛋白从钙粘附素中释放出来。AIM3旨在测试ARF6在黑色素瘤形成和转移中的作用，在已建立的小鼠遗传模型中，该模型概括了人类黑色素瘤的分子病因。这些研究将有助于确定控制黑色素瘤生长和转移的分子机制，阐明ARF6在已建立的致癌途径(Wnt/-连环蛋白、BRAF/MAPK和PI3K/AKT)中的作用，并揭示小GTP酶ARF6是连接这些臭名昭著的途径的纽带。