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: 9223675
• 负责人: Naoki Oshimori
• 金额: $ 24.9万
• 依托单位: OREGON HEALTH & SCIENCE 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 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223675
• 关键词: Academia; Acceleration; Address; Behavior; Bioinformatics; Biometry; Cancer Biology; Carcinoma; Cell Maintenance; Cell Separation; Cell physiology; Cells; ChIP-seq; Clinical Research; Collection; Confocal Microscopy; Data; Disease; Doxycycline; Educational workshop; Ensure; Environment; Epidermis; Epithelial; 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; PPBP gene; 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; Stem cells; System; Tamoxifen; Technical Expertise; Testing; Therapeutic; Time; Tissues; Training; Transforming Growth Factor beta; Transgenic Mice; Tumor Suppressor Proteins; Tumor stage; Universities; University resources; Work; anticancer research; base; cancer stem cell; equipment training; experience; experimental study; extracellular; genetic manipulation; in vivo; interest; knock-down; lectures; loss of function; medical schools; migration; neoplastic cell; next generation; novel; originality; overexpression; post-doctoral training; programs; public health relevance; 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-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且原创的研究项目。具体来说，我感兴趣的是干细胞如何处理来自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常见的信号通路促进肿瘤生长和恶性转化。我对博士后培训剩余时间的计划是获得额外的技能并开发研究工具，我将这些工具带到学术界的独立地位。我的长期研究目标是以皮肤表皮和 TGF-β 信号传导为模型，了解静止干细胞在组织再生过程中如何被激活，以及干细胞的失调如何导致癌症等疾病。人们越来越认识到，许多上皮癌，包括皮肤表皮癌，都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β (TGF-β)，其失调可导致癌症。我已经证明，TGF-β 通过抵消抑制性 BMP 信号传导，诱导静止干细胞增殖和迁移，从而在毛囊再生中发挥关键作用。在皮肤癌中，TGF-β 信号传导具有双重作用：抑制增殖 并在早期发挥肿瘤抑制因子的作用，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 人们对肿瘤知之甚少。我的初步结果表明，TGF-β 信号传导在毛囊和晚期肿瘤的上皮基质界面上都很突出，正常干细胞和癌症干细胞分别驻留在此处。因此，我推测TGF-β具有癌症干细胞特异性功能，并影响晚期的增殖、侵袭和转移潜力。 阶段肿瘤。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-β 信号传导，以及自发表皮肿瘤中的谱系追踪实验。该系统将有助于揭示 TGF-β 在生理环境下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-β 靶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，我的研究最初将基于确定 TGF-β 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。我预计从拟议的研究中获得的信息将为破坏恶性转化、侵袭和转移的各个步骤提供途径。我将在随后向 NIH（NIAMS 和 NCI）和其他可用资金来源申请拨款支持时使用这些发现。作为洛克菲勒大学伊莱恩·福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成长，获得更多的技术专业知识，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，为开展癌症生物学研究、与其他科学家互动以及参加各种讲座提供了无与伦比的环境。字段。三机构小组还在 生物信息学和生物统计学，以及专门针对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拥有良好的记录，我与我们实验室的其他三名博士后研究员合作进行皮肤癌研究。福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。