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（由适用提供）：候选人：I，Allie H. Grossmann，医学博士学位，是犹他大学解剖病理学和肿瘤学系的病理学系教练。我的临床实践包括分子肿瘤学和手术病理学中的骨与软组织专科服务（联合20％的全职专业工作）。我的主要专业努力集中在癌症转移生物学的研究（75％）上。我们最近发表了有关该主题的发现，标题为“小GTPase ARF6在Wnt5a介导的黑色素瘤侵袭和转移过程中刺激β-catenin转录活性” 1。这项工作为我目前的研究奠定了基础，如本提案中概述的，该提案由病理学系资助。我的导师包括Sheri Holmen博士和MD博士学位的Dean Y. Li。我先前的研究经验是在俄勒冈州健康与科学大学的研究经验，我是R. Michael Liskay博士的研究助理，研究DNA不匹配维修，以及医学博士Brian J. Druker的研究生，研究了蛋白质酪氨酸激酶的催化底物特异性。在接下来的5年中，我的直接职业目标包括学习和实施技术来创建有条件的遗传鼠标模型，更新和扩大我对癌症生物学，转移和癌症基因组学的知识，逐渐熟练授予写作，完成此建议中概述的目的，发布结果，确保GRANTS，确保我的实验室人员，扩大RO1的实践，并为我的临床应用程序增添了临床应用程序，并为我的临床实践增强了我的临床效果。我的长期职业目标包括对发现治疗癌症转移的治疗靶标进行研究，开发临床分子测试，以鉴定有疾病进展风险的患者以及临床分子测定的临床分子测定，以识别出可行的干预靶标，并训练下一代医师和科学家。环境：我的导师包括犹他大学亨斯曼癌症研究所（HCI）的外科手术系副教授Sheri L. Holmen，以及犹他大学的医学，人类遗传学和医学博士学位教授的Dean Y. Li。 Holmen博士为我提供了实验室空间，以及包括Wnt/ß-catenin在内的基因工程小鼠模型和癌症信号传导的专家。 Li博士在与ARF6相关的信号，访问独特的ARF6途径试剂中提供专业知识，并在混合物理科学家的双重作用方面提供了智慧。我的咨询委员会由Jan Christian博士（神经生物学和解剖学和内科医学教授），Charles Murtough，PhD（人类遗传学副教授），Richard Dorsky，PhD博士（神经生物学和解剖学副教授），Matthew Vanbrocklin，Matthew Vanbrocklin，Phd，Phd（Surgery of Surigery）和Rodney STECRISICERISIDER（RODNEY STERICERISION），以及STEW的助理（Rodney STEW），STEW。这些研究者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。我的部门主席，医学博士彼得·詹森（Peter Jensen）以及病理学系的其他临床同事和导师，得到了我的研究努力的完全支持，并努力确保我根据需要有临床指导，并保证了受保护的研究时间。我在亨斯曼癌症研究所的Holmen Lab中有实验室空间，该研究所设有来自多个部门的调查人员以及我的一些临床活动的发生。 HCI靠近Li博士的实验室所在的Eccles人类遗传学研究所以及其他供我咨询委员会成员的研究建筑物。研究：控制癌症进展的途径的描述对于发现新目标和改善癌症存活方面的进展至关重要。最近，我们发现了一种新型的信号通路，通过Wnt5a/frizzled4激活了小的GTPase ADP核糖基化因子6（ARF6），从N-钙粘着蛋白中释放β-catenin，从而支持从广告到转录和促进蛋白的入侵和促进蛋白侵袭和转移的梅拉诺瘤的转换中的开关。这项研究的目的是确定Howarf6协调并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ß-catenin激活联系起来。此外，我们已经在体内建立了ARF6与已知的黑色素瘤驱动因素之间的关系。致癌BRAF和PI3K/AKT途径]。目的1和2专注于确定Wnt如何激活ARF6，以及这种激活如何导致转录活性β-catenin从钙粘蛋白释放。 AIM3旨在测试ARF6在黑色素瘤形成和转移中的作用，在概括人类中黑色素瘤分子病因的已建立遗传小鼠模型中。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，并揭示了小型GTPase ARF6是连接这些臭名昭著的链接的小型GTPase ARF6。