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）：候选人：我，艾莉H。Grossmann，医学博士，是犹他州大学病理学系解剖病理学和肿瘤学系的讲师。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亚专业服务（结合20%的全职专业工作）。我的主要专业工作集中在研究（75%）癌症转移的生物学。我们最近发表了关于这个主题的研究结果，标题为“The small GTdR ARF 6 stimulates β- catenin transcriptional activity during WNT 5A-mediated melanoma invasion and metastasis“1。这项工作为我目前的研究提供了基础，如本提案所述，该提案由病理学系资助。我的导师包括Sheri霍尔门博士和Dean Y。Li，MD PhD.我之前的研究经历是在俄勒冈州健康与科学大学，在那里我是R。Michael Liskay博士研究DNA错配修复，Brian J. Druker博士的研究生研究蛋白酪氨酸激酶的催化底物特异性。我在未来5年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，精通赠款写作，完成本提案中概述的AIMS，发表结果，获得赠款，扩大我的实验室人员，生成RO 1应用程序，在我的临床实践中创造卓越。我的长期职业目标包括建立一个调查发现治疗癌症转移的治疗靶点的企业，开发识别疾病进展风险患者的临床分子测试，以及识别干预可行靶点的临床分子测定，并培训下一代医生和科学家。环境：我的导师包括Sheri L。犹他州大学亨茨曼癌症研究所（HCI）外科系副教授、研究员霍尔门博士和迪安Y。李博士，医学博士，犹他州大学医学、人类遗传学和肿瘤学教授。霍尔门博士为我提供了实验室空间和黑色素瘤和癌症信号传导的基因工程小鼠模型的专业知识，包括WNT/β-连环蛋白。李博士提供ARF 6相关信号传导方面的专业知识，获得独特的ARF 6通路试剂，以及融合医生科学家双重角色的智慧。我的咨询委员会由Jan Christian博士（神经生物学与解剖学和内科学教授），Charles Murtaugh博士（人类遗传学副教授），Richard Dorsky博士（神经生物学和解剖学副教授），Matthew VanBrocklin博士（外科助理教授）和Rodney Stewart博士（肿瘤科学助理教授）组成。这些研究人员共同提供发育和癌症信号传导和生物学，各种体内模型以及黑色素细胞和黑色素瘤特异性生物学方面的专业知识。我的系主任，彼得詹森，医学博士，以及其他临床同事和导师在病理学系，是完全支持我的研究工作，并努力确保我有临床指导，根据需要和保证保护时间的研究。我在亨茨曼癌症研究所的霍尔门实验室有一个实验室，那里有来自多个部门的研究人员，我的一些临床活动也在那里进行。HCI与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非常接近。研究：控制癌症进展的通路的描绘对于发现新靶点和改善癌症存活率的进展至关重要。最近，我们发现了一种新的信号传导途径，其中小的GT3 ADP核糖基化因子6（ARF 6）被WNT 5A/Frizzled 4激活以从N-钙粘蛋白释放β-连环蛋白，促进β-连环蛋白功能从粘附到转录的转换，并促进黑素瘤的侵袭和转移1。这项研究的目的是确定ARF 6如何协调和连接多种癌症信号通路。[New该项目的进展揭示了ARF 6激活下游的潜在机制，该机制将PI 3 K/AKT信号传导与β-连环蛋白激活联系起来。此外，我们已经建立了ARF 6和体内黑色素瘤的已知驱动因素之间的关系;致癌BRAF和PI 3 K/AKT通路]。目标1和2集中于确定WNT如何激活ARF 6以及这种激活如何导致钙粘蛋白释放转录活性β-连环蛋白。AIM 3旨在测试ARF 6在已建立的遗传小鼠模型中黑色素瘤形成和转移中的作用，该模型概括了人类黑色素瘤的分子病因学。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，描述ARF 6在已建立的致癌途径（WNT/β-连环蛋白，BRAF/MAPK和PI 3 K/AKT）中的作用，并揭示小GTGF-ARF 6是连接这些臭名昭著的途径的纽带。