The progression of cancer from benign primary tumors to malignant metastatic lesions is achieved through intricate interplay of diverse signaling pathways. One of these pathways, Hippo, is particularly interesting because it has been shown to function both in tumor suppression and in tumor formation based upon context. The mechanisms that orchestrate these opposing roles in cancer remain unknown. In preliminary experiments, I have discovered that YAP, a transcription co-activator and key downstream effector of the Hippo pathway, is highly expressed and nuclear in the basal cells of benign papilloma tumors of the skin. In striking contrast, YAP becomes cytoplasmic in the basal cells of malignant squamous cell carcinomas (SCCs). Since it is the basal cells of both papillomas and SCCs that possess the proliferative, tumor-initiating potential, this suggests that if YAP functions in malignant progression, either its loss from the nucleus or its gain in the cytoplasm must be critical. In this proposal, I aim to 1) Determine the biological importance of YAP in epidermal homeostasis, papilloma formation and SCC development, 2) Probe the role of nuclear YAP in papilloma formation, 3) Elucidate YAP/TEAD targets in papillomas, 4) Identify which targets are critical to skin tumorigenesis and 5) Decipher upstream regulator(s) responsible for YAP localization in papilloma versus SCC, and establish their physiological relevance. Through this study, I hope to reveal how YAP functions in skin homeostasis and malignancy, and shed light on current paradoxes regarding YAP's roles in cancer.
Skin cancer is the most common form of cancer in the United States, with over 3.5 million cases being diagnosed annually. Squamous cell carcinomas (SCCs), in particular, are associated with a substantial risk of metastasis, leading to poor patien prognosis. Understanding the molecular mechanisms involved in the progression of SCCs is critical in developing targeted therapeutics. This proposal aims to contribute to these efforts by using skin as a model to define the molecular changes that occur during progression from normal skin to benign primary tumors to malignant SCCs. Specifically, this proposal centers on elucidating the physiological significance of YAP, a potent transcription co-activator that I have discovered displays distinct expression and localization patterns in papilloma versus SCC. By elucidating the underlying molecular mechanisms, key downstream targets and main regulators involved, I anticipate revealing important new insights into the mechanism of SCC formation/maintenance. My studies, if successful, are likely to provide new therapeutic avenues for diagnosis and treatments of SCCs.
