Elucidating determinants of metastasis suppression in pancreatic cancer

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT CANDIDATE: As a postdoctoral fellow in Dr. Scott Lowe's lab at Memorial Sloan Kettering Cancer Center (MSKCC), my research has focused on the contribution of recurrent genetic lesions to metastasis in pancreatic ductal adenocarcinoma (PDAC). My long-term goal is to establish an independent research program that aims to identify and mechanistically understand metastasis determinants in PDAC, with the ultimate goal of exploiting this knowledge for therapeutic benefit. The proposed research will form a solid foundation on which I can establish my own research group by the end of the mentored phase of this award. I have developed a detailed training plan to ensure my successful transition to independence, which focuses on four key areas: (1) scientific and career mentorship; (2) acquisition of additional knowledge and expertise; (3) professional development; and (4) launching a lab and separation from mentor. RESEARCH: Metastasis is the major cause for the high morbidity and mortality of PDAC, yet few determinants of this metastatic proclivity have been identified. Genomic studies have produced catalogs of recurrent mutations in PDAC, but the functional contribution of common genetic lesions to metastasis remains unclear. My early postdoctoral work has shown how two of these lesions, loss of Smad4 and deletions at the Cdkn2a locus, remove potent barriers to metastasis. By employing novel mouse models, I have discovered that restoration of Smad4 expression can disrupt established liver metastases, and a cluster of type I interferon (IFN) genes that are frequently co-deleted with Cdkn2a suppress metastasis by enforcing tumor immune surveillance. This proposal will test the hypothesis that Smad4, type I IFNs, and other recurrently deleted genes cooperate to inhibit PDAC metastasis through a combination of tumor cell autonomous and non- autonomous mechanisms. I will leverage innovative in vivo platforms to elucidate the mechanisms of metastasis suppression by Smad4 (Aim 1), and to identify genes that cooperate with type I IFNs to block metastasis (Aim 2). These studies will illuminate molecular and cellular programs that suppress metastasis in PDAC, which could inform new strategies for therapeutic intervention in advanced disease. ENVIRONMENT: MSKCC provides an ideal environment for me to accomplish my training and research goals, and successfully transition to an independent faculty position at an academic institution. My mentor Dr. Lowe is a world leader in cancer biology, with a particular expertise on tumor suppressor genes, mouse models, and functional genetics. In addition, I have assembled an advisory committee of three established scientists with relevant expertise and strong commitment to mentoring (Drs. Massagué, Rudensky, and Iacobuzio-Donahue), who will support my transition to independence by providing valuable research and career guidance. Together with the collaborative environment and broad spectrum of resources at MSKCC, this support network creates optimal conditions for the successful completion of the proposed research and career development plans.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Metastasis is the leading cause for the high morbidity and mortality of pancreatic cancer, yet the determinants of this metastatic proclivity remain largely unknown. This project focuses on identifying factors and mechanisms that normally act to suppress metastasis but are frequently disrupted in pancreatic tumors. These studies will improve our understanding of natural barriers that cancer cells overcome to metastasize, with the ultimate goal of informing strategies to restore anti-metastatic programs for therapeutic benefit.