Embryonic signaling pathways in development, regeneration, and cancer
Andrzej Dlugosz, MD
The long-term goal of Dr. Dlugosz's laboratory 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 cancer. Although much of the work is performed using skin as a model system, the underlying principles should be relevant to other organ systems.
Hedgehog signaling pathway
The main research focus is the Hedgehog signaling pathway, which regulates a broad range of embryonic processes including hair follicle development. In adults, aberrant Hedgehog signaling is associated with the formation of skin tumors called basal cell carcinomas, the most common cancers in humans. Deregulated Hedgehog signaling has also been implicated in the development of a subset of tumors arising in various internal sites, including the brain, lung, gastrointestinal tract, and prostate.
Secreted Hedgehog proteins normally influence responsive 'target cells' by binding and antagonizing the function of Patched (Ptch), a transmembrane receptor that blocks the activity of a signaling effector called Smoothened (Smo). Hedgehog-mediated derepression of Smo leads to reprogramming of gene expression in target cells. Whereas Hedgehog signaling is under tight spatial and temporal control during embryogenesis, this pathway is constitutively activated in basal cell carcinomas and other cancers. Pathogenic activation of Hedgehog signaling may be brought about via several mechanisms, including loss-of-function mutations affecting Ptch, gain-of-function mutations in Smo, or uncontrolled, high-level expression of Hedgehog proteins (see Fig. 1).
Fig. 1. Highly simplified model of the Hedgehog (Hh) signaling pathway, depicting GLI as a key transcriptional effector under (A) physiologic (normal) conditions and in cancer (B).
Studies are aimed at better understanding how alterations in the Hedgehog pathway contribute to cancer development and maintenance, and whether targeting this pathway could provide a means of treating Hedgehog-associated malignancies. In addition, the physiologic roles of Hedgehog signaling in the development and growth of hair follicles, and other cell types in skin, are being investigated.
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Hair follicle biology
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 Hedgehog signaling stimulates growth of follicle epithelium by acting directly on stem cells, their progeny, or both; and determining the precise function of Hedgehog signaling in sebaceous gland development and maintenance. Given the widespread importance of Hedgehog signaling in embryogenesis and cancer development, research findings in the hair follicle are likely to lead to a deeper understanding of physiologic and pathologic Hedgehog signaling in a variety of other organs.
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Basal cell carcinoma
Another major focus in the Dlugosz lab is on gaining insight into the causes of cancer, focusing specifically on the role of aberrantly activated embryonic signaling pathways in tumor development. Dr. Dlugosz's team has established a novel mouse model for BCC by overexpressing the transcription factor Gli2 in skin. Using "gene-switch" mice, they have also shown that continued Gli2 expression is required for growth and survival of the majority of tumor cells in established basal cell carcinomas (Fig. 2). Current studies are aimed at advancing the understanding of basal cell carcinoma biology by determining where (progenitor cell population), when (relative to the hair growth cycle), and how (downstream effectors) these tumors develop.
Fig. 2. Regression of tail BCC in Gli2-expressing "gene switch" mice. Gross appearance of BCC during a three week period following shut-down of oncogenic Gli2 expression. Movie was created using photographs taken prior to (Day 0) and after (Day 1, 3, 7, and 21) Gli2 inactivation. The greatest reduction in tumor volume occurs between days 3 and 7, corresponding to a period of intense programmed cell death within the tumor.
View a movie of this regression
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Hedgehog signaling and internal cancers
In the course of his skin-related research studies, Dr. Dlugosz has found evidence supporting a role for Hedgehog signaling in the development of cancers arising in several other organs. The current emphasis of these studies is on cancers arising in the head and neck region, using "gene-switch" mice which allow precise regulation of gene expression in a spatially- and temporally-controlled manner. Insights from these studies are likely to provide new knowledge into the role of Hedgehog signaling in head and neck biology and cancer.
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