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

点击翻译按钮获取中文摘要

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¿ 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.