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

• 批准号: 8567626
• 负责人: Naoki Oshimori
• 金额: $ 16.09万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-08 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8567626
• 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; Critiques; 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; 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; Transforming Growth Factors; Transgenic Mice; Tumor Suppressor Proteins; Tumor stage; United States National Institutes of Health; Universities; Work; Writing; anticancer research; base; cancer stem cell; experience; extracellular; genetic manipulation; in vivo; interest; lectures; loss of function; medical schools; meetings; migration; neoplastic cell; next generation; novel; originality; overexpression; post-doctoral training; programs; public health relevance; research study; response; skills; small hairpin RNA; stem cell biology; stem cell population; tissue regeneration; tool; transcriptome sequencing; tumor; tumor growth; tumor progression; tumorigenesis

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¿ 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 ¿ (TGF¿). I have shown that TGF¿ 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¿ 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¿ can elicit different cellular responses in early and late-stage tumors is poorly understood. My preliminary results suggest that TGF¿ 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¿ 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¿ 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¿ in tumor progression in a physiological setting. I expect that the originality of my approach and identification of TGF¿ 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¿ 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）：在我的研究生和博士后培训，我的目标一直是获得经验，这将使我能够建立一个独立的和原始的干细胞和癌症生物学研究计划。具体来说，我感兴趣的是干细胞如何处理来自其微环境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肿瘤生长和恶性转化的共同信号传导途径。我的博士后培训的其余部分的计划是获得额外的技能和开发研究工具，我将带来一个独立的位置在学术界。我的长期研究目标是了解静止的干细胞如何在组织再生过程中被激活，以及干细胞的失调如何导致癌症等疾病，使用皮肤表皮和TGF信号作为模型。越来越多的人认识到，许多上皮癌，包括皮肤表皮癌，是由干细胞群引起的，利用这些特性为癌症治疗策略提供了一个新的框架。表皮干细胞的一个关键调节因子是转化生长因子（TGF），其失调可导致癌症。我已经证明，TGF？在毛囊再生中起关键作用，诱导静止干细胞增殖，并通过抵消抑制性BMP信号传导迁移。在皮肤癌中，TGF β信号具有双重作用：它抑制增殖 并且在早期作为肿瘤抑制物起作用，但在晚期肿瘤中促进肿瘤生长、侵袭和转移。然而，TGF β如何在早期和晚期引起不同的细胞反应， 对肿瘤了解甚少。我的初步结果表明，TGF β信号在毛囊和晚期肿瘤的上皮-基质界面都很突出，正常干细胞和癌症干细胞分别位于该界面。因此，我假设TGF β具有癌症干细胞特异性功能，并影响晚期肿瘤干细胞的增殖、侵袭和分化潜能。 肿瘤分期为了验证这一假设，我将创建一个新的实验系统，该系统允许在单细胞水平上可视化和操纵TGF？信号传导，并在自发性表皮肿瘤中进行谱系追踪实验。该系统将有助于揭示TGF β在生理环境中肿瘤进展中的细胞自主作用。我希望我的方法的独创性和TGF？靶点的确定将使我能够为未来的研究计划奠定坚实的基础。在我自己的实验室里，我将首先把我的研究建立在确定TGF β下游靶点如何调节晚期肿瘤进展和癌症干细胞行为的机制上。我希望从拟议的研究中获得的信息将提供破坏恶性转化，侵袭和转移的各个步骤的途径。我将在随后向NIH（NIAMS和NCI）和其他可用资金来源申请资助时使用这些发现。作为洛克菲勒大学伊莱恩·富克斯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，获得更多的技术专长，并生成有助于我未来研究的材料。该大学是三机构计划的一部分，与纪念斯隆-凯特琳癌症中心和威尔-康奈尔医学院一起，这是一个无与伦比的环境，可以进行癌症生物学研究，与其他科学家互动，并参加各种领域的讲座。三方机构小组还在下列国家举办讲习班： 生物信息学和生物统计学，以及致力于临床和癌症研究的讲座，这些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有着良好的记录，我与我们实验室的其他三名博士后合作进行皮肤癌研究。富克斯实验室和大学资源中心的许多资源将提供设备，培训和技术专业知识，以确保成功完成拟议的研究。