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

描述（由申请人提供）：候选人：我，Allie H. Grossmann，医学博士，是犹他大学解剖病理学和肿瘤学分部病理学系的讲师。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（合计20%的全职专业工作）。我的主要专业工作集中在癌症转移生物学方面的研究（75%）。我们最近发表了关于这一主题的研究结果，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提供了基础，正如这份提案所概述的那样，该提案由病理学部资助。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，在那里我是R. Michael Liskay博士的研究助理，研究DNA错配修复，以及Brian J. Druker博士的研究生，研究蛋白质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条件遗传小鼠模型的创建技术，更新和扩展我在癌症生物学、转移和癌症基因组学方面的知识，精通拨款写作，完成本提案中概述的AIMS，发表结果，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。我的长期职业目标包括建立一个研究发现治疗癌症转移的治疗靶点的企业，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Sheri L. Holmen博士，犹他大学外科系副教授和亨茨曼癌症研究所（HCI）研究员，以及Dean Y. Li，医学博士，犹他大学医学、人类遗传学和肿瘤学教授。Holmen博士为我提供了黑素瘤和癌症信号的基因工程小鼠模型（包括WNT/ß-catenin）的实验室空间和专业知识。李博士提供ARF6相关信号的专业知识，获得独特的ARF6途径试剂，以及融合医师科学家双重角色的智慧。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）、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（肿瘤学助理教授）组成。这些研究人员在发育和癌症信号和生物学、各种体内模型、黑素细胞和黑素瘤特异性生物学方面提供专业知识。我的系主任，Peter Jensen医学博士，以及病理学系的其他临床同事和导师都全力支持我的研究工作，并努力确保我在需要的时候得到临床指导，并保证有保护的研究时间。我在亨茨曼癌症研究所的霍尔曼实验室有实验室，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靠近埃克尔斯人类遗传学研究所（埃克尔斯研究所是李博士的实验室所在地）和我的咨询委员会成员居住的其他研究大楼。研究：描述控制癌症进展的途径对于发现新的靶点和改善癌症生存至关重要。最近，我们发现了一个新的信号通路，即小GTPase ADP核糖基化因子6 （ARF6）被WNT5A/Frizzled4激活，从N-cadherin释放ß-catenin，促进ß-catenin功能从粘附到转录的转换，促进黑色素瘤a1的侵袭和转移。本研究的目的是确定warf6如何协调和连接多种癌症信号通路。[该项目的新进展揭示了ARF6激活下游的潜在机制，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与黑色素瘤已知驱动因素之间的关系；致癌BRAF和PI3K/AKT通路]。AIMS 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钙粘蛋白释放转录活性ß-catenin。AIM3旨在通过已建立的遗传小鼠模型测试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，描绘ARF6在既定的致癌途径（WNT/ß-catenin， BRAF/MAPK和PI3K/AKT）中的作用，并揭示小GTPase ARF6是连接这些臭名昭着的途径的链接。

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.