Elucidating determinants of metastasis suppression in pancreatic cancer

项目总结/摘要 候选人：作为纪念斯隆凯特琳癌症中心斯科特·洛博士实验室的博士后研究员， （MSKCC），我的研究集中在复发性遗传性病变对胰腺癌转移的贡献， 导管腺癌（PDAC）。我的长期目标是建立一个独立的研究计划， 识别并从机制上理解PDAC中的转移决定因素，最终目标是 将这些知识用于治疗益处。拟议的研究将形成一个坚实的基础上，我 在这个奖项的指导阶段结束之前，我可以建立自己的研究小组。我开发了一个 详细的培训计划，以确保我成功过渡到独立，该计划侧重于四个关键领域： 科学和职业指导;（2）获得更多的知识和专业知识;（3）专业 开发;（4）启动实验室并与导师分离。 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 这种转移倾向已经被确定。基因组研究已经产生了一系列反复出现的 PDAC中的突变，但常见的遗传性病变转移的功能贡献仍然不清楚。 我早期的博士后工作已经表明，这些病变中的两个，Smad 4的丢失和Cdkn 2a的缺失， 基因座，消除转移的潜在障碍。通过使用新的小鼠模型，我发现， Smad 4表达的恢复可以破坏已建立的肝转移，并且I型干扰素簇 (IFN)经常与Cdkn 2a共缺失的基因通过增强肿瘤免疫抑制转移 监视该提案将检验Smad 4、I型IFN和其他经常性缺失的IFN-γ基因的假设。 基因通过肿瘤细胞自主性和非自主性的结合来合作抑制PDAC转移。 自主机制。我将利用创新的体内平台来阐明 通过Smad 4（Aim 1）的转移抑制，并鉴定与I型IFN合作阻断肿瘤转移的基因。 转移（目的2）。这些研究将阐明抑制肿瘤转移的分子和细胞程序， PDAC可以为晚期疾病的治疗干预提供新的策略。 环境：MSKCC为我提供了一个理想的环境，以实现我的培训和研究目标， 并成功过渡到学术机构的独立教师职位。我的导师洛博士 癌症生物学领域的世界领导者，在肿瘤抑制基因、小鼠模型和 功能遗传学此外，我还召集了一个由三位知名科学家组成的咨询委员会， 相关的专业知识和对指导的坚定承诺（Massagué博士、Rudensky博士和Iacoquinio-Donahue博士）， 他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。一起 利用微软科学、技术和文化中心的协作环境和广泛的资源，这个支持网络 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.