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: 9294989
• 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/9294989
• 关键词: ADP-ribosylation factor 6; Adaptor Signaling Protein; Adherens Junction; Adhesions; Advisory Committees; Anatomy; BRAF gene; Biological Assay; Biology; Bone Tissue; Cadherins; Cancer Biology; Clinical; Committee Members; DNA; Data; Databases; Department chair; Development; Disease Progression; Doctor of Philosophy; Ensure; Enterobacteria phage P1 Cre recombinase; 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; Health Sciences; Human; Human Genetics; Huntsman Cancer Institute at the University of Utah; In Vitro; Incidence; Institutes; Internal Medicine; Intervention; Investigation; Knowledge; Laboratories; Laboratory Personnel; Learning; Link; MAP Kinase Gene; Maintenance; Malignant Neoplasms; Maps; Mediating; Medicine; Melanosis; 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; Pharmacology; Phosphorylation; Phosphorylation Site; Phosphoserine; Phosphotransferases; Physicians; Play; Protein Tyrosine Kinase; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Reagent; Recording of previous events; Recruitment Activity; Research; Research Assistant; Research Personnel; Role; Scaffolding Protein; Science; Scientist; Secure; Serine; Services; Signal Pathway; Signal Transduction; Site; Subcutaneous Injections; Substrate Specificity; Surgical Pathology; System; Techniques; Testing; Threonine; Time; Training; Transactivation; Tyrosine; Tyrosine Phosphorylation; United States; Universities; Update; Utah; Virus; WNT Signaling Pathway; WNT5A gene; Woman; Work; Writing; alpha catenin; beta catenin; beta-arrestin; cancer genomics; cancer subtypes; cancer survival; career; clinical practice; design; disorder risk; experience; graduate student; improved; in vivo; in vivo Model; instructor; knock-down; melanocyte; melanoma; member; men; mid-career faculty; molecular oncology; mouse model; new therapeutic target; next generation; novel; oncology; professor; public health relevance; receptor; 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/ß-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 ß-catenin from N-cadherin, facilitating a switch in ß-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 ß-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 ß-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/ß-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，Allie H. Grossmann，医学博士、博士，是犹他大学病理学系、解剖病理学和肿瘤学部的讲师，我的临床实践包括分子肿瘤学和骨骼学。 & 外科病理学软组织专科服务（结合 20% 的全职专业工作） 我的主要专业工作集中在生物学研究（75%）。我们最近发表了关于该主题的研究结果，标题为“小 GTP 酶 ARF6 在 WNT5A 介导的黑色素瘤侵袭和转移过程中刺激 β-连环蛋白转录活性”1。这项工作为我当前的研究奠定了基础。 ，由病理学系资助。我的导师包括 Sheri Holmen 博士和 Dean Y. Li 博士。我之前的研究经历是在俄勒冈健康与科学大学，当时我是 R. Michael 的研究助理。 Liskay 博士，研究 DNA 错配修复，以及 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。我未来 5 年的近期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，精通资助写作，完成本提案中概述的目标，发表结果，获得资助，扩大我的实验室人员，产生 RO1我的长期职业目标包括建立一个研究企业，以发现治疗癌症转移的治疗靶点，开发识别有疾病进展风险的患者的临床分子测试，以及临床分子检测确定可行的干预目标，并培训下一代医生和科学家 环境：我的导师包括犹他大学亨斯曼癌症研究所 (HCI) 外科副教授兼研究员 Sheri L. Holmen 博士。和 Dean Y. Li 医学博士犹他大学医学、人类遗传学和肿瘤科学教授 Holmen 博士为我提供了黑色素瘤和癌症信号转导小鼠模型的实验室空间和专业知识，包括 Li 博士提供的 WNT/ß-catenin。我的顾问委员会由 Jan Christian 博士（神经生物学、解剖学和内科学教授）组成。医学）、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）这些研究人员共同提供了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。与病理学系的其他临床同事和导师一样，他们全力支持我的研究工作，并努力确保我获得所需的临床指导并保证我在亨斯曼癌症中心的霍尔门实验室拥有实验室空间。 HCI 靠近李博士实验室所在的埃克尔斯人类遗传学研究所，以及我的咨询委员会成员所在的其他研究大楼。 ： 划定控制癌症进展的途径对于新靶标的发现和改善癌症生存的进展至关重要。最近，我们发现了一种新的信号传导途径，通过 WNT5A/Frizzled4 激活小 GTP 酶 ADP 核糖基化因子 6 (ARF6)，从 N 中释放 β-连环蛋白。 -钙粘蛋白，促进β-连环蛋白功能从粘附到转录和促进黑色素瘤的侵袭和转移的转变。 [该项目的新进展揭示了 ARF6 激活下游的潜在机制，将 PI3K/AKT 信号传导与 ß-连环蛋白激活联系起来。此外，我们还建立了 ARF6 与已知的体内黑色素瘤驱动因素之间的关系。致癌 BRAF 和 PI3K/AKT 通路 AIMS 1 和 2 重点确定 WNT 如何激活 ARF6 以及这种激活如何导致转录活性 ß-catenin 的释放。来自钙粘蛋白的ARF6旨在在已建立的遗传小鼠模型中测试ARF6在黑色素瘤形成和转移中的作用，这些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，描述其作用。 ARF6 在已建立的致癌途径（WNT/ß-catenin、BRAF/MAPK 和 PI3K/AKT）中的作用，并揭示了小 GTPase ARF6 是连接这些臭名昭著的通路的纽带。