Wnt signaling and skin cancer; Merkel cell carcinoma pathogenesis
Monique Verhaegen, PhD and Andrzej A. Dlugosz, MD
Dr. Verhaegen carries out research in the laboratory of Dr. Andrzej Dlugosz whose laboratory's long-term goal is to gain a better understanding of how embryonic signaling pathways control normal growth and development, and how deregulation of these pathways can lead to pathological responses including cancer. One of their main interests is the Hedgehog (Hh) signaling pathway; trying to understand how normal signaling regulates various embryonic processes including hair follicle development, whereas deregulated signaling leads to basal cell carcinoma of the skin as well as a subset of internal tumors. Because recent studies from this laboratory have established a central role for the canonical Wnt/Beta-catenin signaling pathway in Hh pathway-driven growth of benign skin tumors, Dr. Verhaegen is now exploring the interaction between these pathways in the development and maintenance of malignant skin tumors. Dr. Verhaegen is also developing a separate research program studying mechanisms associated with the pathogenesis of Merkel cell carcinoma (MCC), a rare, but highly aggressive skin cancer.
Crosstalk between Hedgehog and canonical Wnt/Beta-catenin pathway signaling
Overactivation of the Hh signaling pathway plays a central role in the development of several human tumors, including basal cell carcinomas (BCC) and benign basaloid follicular hamartomas. Both of these tumors express multiple Wnt ligands, leading to activation of the canonical Wnt/Beta-catenin pathway. While it has recently been shown that follicular hamartomas are strictly dependent on canonical Wnt/Beta-catenin signaling, the role of this second embryonic signaling pathway is unknown in malignant Hh-driven tumors. Dr. Verhaegen's research uses state-of-the art mouse models as well as a potent pharmacological inhibitor of Wnt signaling to further elucidate the relationship between these two embryonic signaling pathways. Ultimately, these studies aim to determine the possible role or requirement of canonical Wnt/Beta-catenin signaling in the pathogenesis of Hh-driven basal cell carcinoma.
Furthermore, uncontrolled Hh activity in human and mouse skin is also associated with increased pigmentation, a well-known clinical phenomenon which is currently not understood. Using a variety of mouse models and other approaches, Dr. Verhaegen is assessing the signaling relationships between keratinocytes and melanocytes during this pathological form of pigmentation, and will define the role of the Wnt pathway, secreted factors involved in melanogenesis, and p53 function in this process. These studies aim to define the molecular mechanisms responsible for this Hh-dependent disrupted pigment production and possibly provide insight with therapeutic potential relevant to disorders of pigmentation.
Pathogenesis of Merkel Cell Carcinoma (MCC)
A major project in the Dlugosz laboratory centers on understanding the interplay of molecular signals controlling growth and differentiation of hair follicles and oil-producing sebaceous glands derived from hair follicles. Dr. Dlugosz's studies have shown that the Hedgehog pathway, which can lead to basal cell carcinoma development when deregulated, is required for hair follicle growth and sebaceous gland formation. Current work is aimed at understanding whether Hh signaling stimulates growth of follicle epithelium by acting directly on stem cells, their progeny, or both; and determining the precise function of Hh signaling in sebaceous gland development and maintenance. Given the widespread importance of Hh signaling in embryogenesis and cancer development, research findings in the hair follicle are likely to lead to a deeper understanding of physiologic and pathologic Hh signaling in a variety of other organs.
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