Elucidating determinants of metastasis suppression in pancreatic cancer

阐明胰腺癌转移抑制的决定因素

• 批准号: 10662194
• 负责人: Kaloyan M. Tsanov
• 金额: $ 13.53万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10662194
• 关键词: Advisory Committees; Affect; Area; Award; CD8-Positive T-Lymphocytes; CDKN2A gene; CRISPR/Cas technology; Cancer Biology; Catalogs; Cells; Data; Development; Development Plans; Disease; Ensure; Environment; Event; Evolution; Faculty; Foundations; Gene Deletion; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Genomics; Goals; Immune; Immunologic Surveillance; Institution; Interferon Type I; Interferons; KRAS2 gene; Knowledge; Lesion; Link; MADH4 gene; Maintenance; Malignant neoplasm of pancreas; Mediating; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Metastasis Suppression; Metastasis Suppressor Genes; Metastatic Neoplasm to the Liver; Molecular; Morbidity - disease rate; Mutation; Natural Killer Cells; Neoplasm Metastasis; Oncogenes; Pancreatic Ductal Adenocarcinoma; Patients; Phase; Population; Positioning Attribute; Postdoctoral Fellow; RNA interference screen; Recurrence; Research; Resources; Role; Scientist; Solid; TP53 gene; Testing; Therapeutic; Therapeutic Intervention; Training; Tumor Promotion; Tumor Suppressor Genes; Tumor stage; Tumor-Suppressor Gene Inactivation; Up-Regulation; Vocational Guidance; Work; advanced disease; cancer cell; cancer type; career; career development; collaborative environment; combinatorial; epigenomics; genetic signature; improved; in vivo; innovation; insight; mortality; mouse model; neoplastic cell; novel; novel therapeutic intervention; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; post-doctoral training; programs; research and development; restoration; spatiotemporal; support network; tool; transcription factor; transcriptomics; tumor

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.

项目摘要/摘要 候选人：作为纪念斯隆·斯特林癌症中心斯科特·洛（Scott Lowe）实验室的博士后研究员 （MSKCC），我的研究重点是复发性病变对胰腺转移的贡献 尘埃腺癌（PDAC）。 识别和机械理解PDAC中的转移和转移决定因素，其最终目标是 利用这一知识以获得治疗益处。 可以在该奖项的指导阶段结束前建立我自己的研究小组。 详细的培训计划，以确保我成功过渡到独立性，该计划侧重于四个关键领域：（1） 科学和职业指导； 开发和（4）与导师一起启动实验室和分离。 研究：转移是PDAC的高病态和死亡率的主要原因，但决定因素很少 已经确定了这种转移性倾向。 PDAC中的突变，但常见遗传病变对转移的功能贡献尚不清楚。 我早期的博士后作品Hus向CDKN2A上的smad4和deltions丢失了两个病变 基因座，通过使用新颖的鼠标来消除转移的有效障碍。 SMAD4表达的恢复可能会破坏已建立的肝脏转移和I型干扰素簇 （IFN）经常与CDKN2A抑制转移的基因通过强制肿瘤免疫 监视。 基因合作通过肿瘤细胞自主和非 - 自主机制。 通过SMAD4抑制转移（AIM 1），并确定与IIIFN型合作以阻止的基因 转移（目标2）。 PDAC，可以向治疗性干预的新策略提供新的策略。 环境：MSKCC为我提供了实现培训和研究目标的理想环境， 并成功地过渡到我的导师Lowe是一个独立的教师职位。 癌症生物学的世界领导者，在肿瘤抑制基因，小鼠模型和 功能性遗传学。 相关的专业知识和对指导的坚定承诺（Massagué博士，Rudensky和Iacobuzio-Donahue）， 谁将通过提供宝贵的研究和职业指导来支持我向独立的过渡 在MSKCC的协作环境和广泛的资源中，此支持网络创建 成功压缩支撑研究和职业发展计划的最佳条件。