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

描述(由申请人提供)：在我的研究生和博士后培训期间，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一个独立和原创的研究项目。具体地说，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来协调组织结构，以及癌症干细胞如何利用常见的信号通路来促进肿瘤生长和恶性转化。我对剩下的博士后培训的计划是获得更多的技能，并开发研究工具，我将把这些工具带到学术界的一个独立位置。我的长期研究目标是以皮肤表皮和转化生长因子信号为模型，了解静止的干细胞在组织再生过程中是如何被激活的，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，许多上皮性癌症，包括皮肤表皮癌症，都是由干细胞群体引起的，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)，它的失调可能导致癌症。我已经证明，转化生长因子β通过抑制BMP信号诱导静止的干细胞增殖和迁移，从而在毛囊再生中发挥关键作用。在皮肤癌中，转化生长因子信号具有双重作用：它抑制增殖 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，转化生长因子如何在早期和晚期引发不同的细胞反应 人们对肿瘤知之甚少。我的初步结果表明，转化生长因子信号在毛囊和晚期肿瘤的上皮-间质界面上都很突出，正常干细胞和癌症干细胞分别驻留在那里。因此，我假设转化生长因子β具有肿瘤干细胞的特异性功能，并影响最近的增殖、侵袭和转移潜能。 分期肿瘤。为了验证这一假设，我将生成一个新的实验系统，允许在单细胞水平上可视化和操作转化生长因子信号，以及自发表皮肿瘤的谱系追踪实验。该系统将有助于在生理环境下揭示转化生长因子在肿瘤进展中的细胞自主作用。我希望我的独创性方法和对转化生长因子目标的确定将使我为未来的研究计划奠定坚实的基础。在我自己的实验室里，我最初的研究将基于确定转化生长因子下游靶标如何调控晚期肿瘤进展和癌症干细胞行为的机制。我期望从拟议的研究中获得的信息将为阻断恶性转化、侵袭和转移的个别步骤提供途径。我将在以后向NIH(NIAMS和NCI)和其他可用的资金来源提出的赠款支持申请中使用这些发现。作为洛克菲勒大学Elaine Fuchs博士的博士后研究员，我处于一个理想的环境中，可以继续我作为科学家和导师的成长，获得更多的技术专长，并产生有助于我未来研究的材料。该大学与纪念斯隆-凯特琳癌症中心和威尔-康奈尔医学院一起，是三所院校计划的一部分，这是一个无与伦比的环境，可以开展癌症生物学研究，与其他科学家互动，并参加各种领域的讲座。三机构小组还在#年组织讲习班。 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，这将继续对我的工作有用。此外，我的导师福克斯博士在表皮干细胞和皮肤癌研究方面有着良好的记录，我与实验室的其他三名博士后研究员合作研究皮肤癌。Fuchs实验室和大学资源中心的许多资源将提供设备、培训和技术专业知识，确保成功完成拟议的研究。

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.