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

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 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.