Dissecting stage-specific roles of TGF-beta in epidermal tumor progression

剖析 TGF-β 在表皮肿瘤进展中的阶段特异性作用

基本信息

批准号：
8698352
负责人：
Naoki Oshimori
金额：
$ 16.09万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-08 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8698352
关键词：
Academia Acceleration Address Behavior Bioinformatics Biometry Cancer Biology Cell Maintenance Cell Separation Cell physiology Cells ChIP-seq Clinical Research Collection Confocal Microscopy Data Diagnostic Neoplasm Staging Disease Doxycycline Educational workshop Ensure Environment Epidermis Epithelial Equipment Foundations Funding Agency Gene Expression Genes Goals Grant Growth Hair follicle structure Health Image Imagery In Situ Individual Kinetics Knock-out Label Laboratories Lead Malignant - descriptor Malignant Conversion Malignant Neoplasms Memorial Sloan-Kettering Cancer Center Mentors Modeling Molecular Molecular Profiling National Institute of Arthritis and Musculoskeletal and Skin Diseases Natural regeneration Neoplasm Metastasis Oncogenic Pathway interactions Patients Pattern Phenotype Physiological Play Population Positioning Attribute Postdoctoral Fellow Proliferating Property Proteins Reporter Research Research Personnel Resources Role Scientist Signal Pathway Signal Transduction Skin Skin Cancer Solid Staging Stem cells System Tamoxifen Technical Expertise Testing Therapeutic Time Tissues Training Transforming Growth Factor beta Transgenic Mice Tumor Suppressor Proteins Tumor stage United States National Institutes of Health Universities Work anticancer research base beta-Thromboglobulin cancer stem cell experience extracellular genetic manipulation in vivo interest lectures loss of function medical schools migration neoplastic cell next generation novel originality overexpression post-doctoral training programs research study response skills small hairpin RNA stem cell biology stem cell population tissue regeneration tool transcriptome sequencing tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Throughout my graduate and postdoctoral training, my goal has been to gain experience that will enable me to establish an independent and original research program in stem cell and cancer biology. Specifically, I am interested in how stem cells process various extracellular signals from their microenvironment to coordinate tissue organization, and how cancer stem cells exploit common signaling pathways for tumor growth and malignant conversion. My plan for the remainder of my postdoctoral training is to acquire additional skills and develop research tools that I will bring to an independent position in academia. My long-term research objective is to understand how quiescent stem cells are activated during tissue regeneration, and how the dysregulation of stem cells can lead to diseases such as cancer, using skin epidermis and TGF-beta signaling as a model. It has become increasingly recognized that many epithelial cancers, including those of the skin epidermis, arise from stem cell populations and exploiting these properties offers a novel framework for cancer therapeutic strategies. One key regulator of epidermal stem cells whose dysregulation can lead to cancer is transforming growth factor beta (TGF-beta). I have shown that TGF-beta plays a pivotal role in hair follicle regeneration by inducing quiescent stem cells to proliferate and migrate by counteracting repressive BMP signaling. In skin cancer, TGF-beta signaling has a dual role: it inhibits proliferation and function as a tumor suppressor early on, but promotes tumor growth, invasion, and metastasis in advanced tumors. However, how TGF-beta can elicit different cellular responses in early and late-stage tumors is poorly understood. My preliminary results suggest that TGF-beta signaling is prominent at the epithelial-stromal interface of both hair follicles and advanced tumors, where normal and cancer stem cells reside, respectively. Therefore, I hypothesize that TGF-beta has a cancer stem cell specific function and influence the proliferative, invasive, and metastastic potential of late stage tumors. To test this hypothesis, I will generate a new experimental system that allows for visualization and manipulation of TGF-beta signaling at the single cell level, together with lineage tracing experiments in spontaneous epidermal tumors. This system will help to uncover the cell autonomous roles of TGF-beta in tumor progression in a physiological setting. I expect that the originality of my approach and identification of TGF-beta targets will allow me to build a solid foundation for a future research program. In my own lab, I will initially base my research on identifying mechanisms of how TGF-beta downstream targets regulate late-stage tumor progression and the behaviors of cancer stem cells. I expect that the information obtained from the proposed research will provide avenues to disrupt individual steps in malignant conversion, invasion, and metastasis. I will use these findings in subsequent grant support applications to the NIH (NIAMS and NCI) and other available sources of funding. As a postdoctoral fellow with Dr. Elaine Fuchs at the Rockefeller University, I am in an ideal environment to continue my growth as a scientist and mentor, to acquire additional technical expertise, and to generate materials that will facilitate my future research. The university is a part of the Tri-Institutional Program, together with Memorial Sloan-Kettering Cancer Center and Weill-Cornell Medical College, which is an unparalleled environment to conduct research in cancer biology, interact with other scientists, and attend lectures in a variety of fields. The Tri-Institutional group also organizes workshops in bioinformatics and biostatistics, and lectures dedicated to clinical and cancer research, which will continue to be useful in my work. Furthermore, my mentor, Dr. Fuchs, has a strong track record in epidermal stem cell and skin cancer research, and I collaborate with three other postdoctoral fellows in our lab on skin cancer studies. The many resources in the Fuchs lab and university resource centers will provide equipment, training, and technical expertise that will ensure successful completion of the proposed research.

描述（由申请人提供）：在我的整个研究生和博士后培训中，我的目标是获得经验，使我能够在干细胞和癌症生物学方面建立独立和原始的研究计划。具体而言，我对干细胞如何处理微环境中的各种细胞外信号以协调组织组织以及癌症干细胞如何利用公共信号通路来实现肿瘤生长和恶性转化率。我对博士后培训的其余计划是获得其他技能，并开发我将在学术界独立职位的研究工具。我的长期研究目标是了解组织再生期间如何激活静态干细胞，以及干细胞的失调如何使用皮肤表皮和TGF-β信号作为模型导致癌症等疾病，例如癌症。人们越来越认识到，许多上皮癌，包括皮肤表皮的癌症，是由干细胞种群引起的，并且利用这些特性为癌症治疗策略提供了新的框架。表皮干细胞的一个关键调节剂的失调可能导致癌症转化生长因子β（TGF-β）。我已经表明，TGF-beta通过诱导静止的干细胞来通过抵消抑制性BMP信号传导来增殖和迁移，在毛囊再生中起关键作用。在皮肤癌中，TGF-β信号传导具有双重作用：它抑制了增殖早期起肿瘤抑制剂的功能，但促进晚期肿瘤中的肿瘤生长，侵袭和转移。但是，TGF-β如何在早期和晚期引起不同的细胞反应肿瘤知之甚少。我的初步结果表明，TGF-β信号在毛囊和晚期肿瘤的上皮界面界面上分别是正常和癌症干细胞驻留的。因此，我假设TGF-β具有癌症干细胞的特异性功能，并影响近来的增殖，侵入性和转移潜力舞台肿瘤。为了检验这一假设，我将生成一个新的实验系统，该系统允许在单细胞水平上可视化和操纵TGF-beta信号，并在自发表皮肿瘤中进行谱系追踪实验。该系统将有助于揭示TGF-β在生理环境中TGF-beta在肿瘤进展中的自主作用。我希望我的方法的独创性和对TGF-beta目标的识别将使我能够为未来的研究计划奠定坚实的基础。在我自己的实验室中，我最初将基于识别TGF-beta下游靶标如何调节晚期肿瘤进展和癌症干细胞行为的机制。我希望从拟议的研究中获得的信息将为破坏恶性转化，入侵和转移的各个步骤提供途径。我将在对NIH（NIAMS和NCI）和其他可用资金来源的随后赠款支持申请中使用这些发现。作为洛克菲勒大学（Rockefeller University）的Elaine Fuchs博士的博士后研究员，我处于一个理想的环境中，可以继续作为科学家和导师的成长，以获得更多的技术专长，并生成将促进我未来研究的材料。该大学是三机构计划的一部分，与纪念斯隆 - 凯特林癌症中心和威尔 - 康奈尔医学院一起，这是一个无与伦比的环境，用于进行癌症生物学研究，与其他科学家进行互动并参加各种领域的讲座。三机构小组还组织研讨会生物信息学和生物统计学以及致力于临床和癌症研究的演讲，这将继续对我的工作有用。此外，我的导师Fuchs博士在表皮干细胞和皮肤癌研究方面具有很强的记录，我在我们的皮肤癌研究实验室中与其他三个博士后研究员合作。 Fuchs实验室和大学资源中心的许多资源将提供设备，培训和技术专长，以确保成功完成拟议的研究。