Elucidating determinants of metastasis suppression in pancreatic cancer

项目摘要/摘要 候选人：斯科特·洛博士在纪念斯隆·凯特琳癌症中心的实验室做博士后 (MSKCC)，我的研究重点是复发的遗传性病变对胰腺转移的贡献。 导管腺癌(PDAC)。我的长期目标是建立一个独立的研究项目，旨在 识别和机械地了解PDAC中的转移决定因素，最终目标是 利用这一知识为治疗带来好处。拟议的研究将为我以下工作奠定坚实的基础 可以在这个奖项的指导阶段结束前建立我自己的研究小组。我已经开发出一种 详细的培训计划，以确保我成功过渡到独立，重点是四个关键领域：(1) 科学和职业指导；(2)获得更多的知识和专长；(3)专业 开发；以及(4)启动实验室并与Mentor分离。 研究：转移是PDAC高发病率和死亡率的主要原因，但很少有决定因素 这种转移倾向的部分已经被发现。基因组研究已经产生了反复发作的 PDAC中的突变，但常见的基因损伤对转移的功能贡献尚不清楚。 我早期的博士后工作显示了其中的两个损伤，Smad4的丢失和CDKN2a的缺失 消除转移的有效障碍。通过使用新的老鼠模型，我发现 Smad4表达的恢复可以阻断已建立的肝转移，以及I型干扰素簇 经常与CDKN2a共缺失的干扰素基因通过增强肿瘤免疫来抑制转移 监视系统。这一提议将检验Smad4、I型IFN和其他递归删除的假设 基因通过肿瘤细胞自主性和非自主性结合抑制PDAC转移 自主机制。我将利用创新的体内平台来阐明 Smad4抑制转移(目标1)，并确定与I型IFN协同作用的基因以阻断 转移(目标2)。这些研究将阐明抑制肿瘤转移的分子和细胞程序。 PDAC，这可能为晚期疾病的治疗干预提供新的策略。 环境：MSKCC为我实现培训和研究目标提供了一个理想的环境， 并成功过渡到学术机构的独立教员职位。我的导师洛博士是 癌症生物学的世界领先者，在肿瘤抑制基因、小鼠模型和 功能遗传学。此外，我还组建了一个由三位知名科学家组成的顾问委员会， 相关专业知识和对指导的坚定承诺(Massagué博士、Rudensky博士和Iaco buzio-Donahue博士) 世卫组织将通过提供有价值的研究和职业指导来支持我向独立的过渡。同舟共济 借助MSKCC的协作环境和广泛的资源，该支持网络创建了 成功完成拟议的研究和职业发展计划的最佳条件。

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.