• Lung Cancer
• Wnt Signalling Pathway
• Bronchioalveolar Carcinoma
• Cancer Stem Cells
• Esophageal Cancer
• Mesothelioma
• Expression Profiling
• Lung Cancer System Genetics
• KRas Pathway
• Other Cancers
• Diagnostics Development

Wingless-int (Wnt) proteins are important secreted signaling molecules that regulate numerous interactions in the cell and affect diverse biological processes from embryogenesis to tumorigenesis. When overexpressed, they appear to contribute to a cascade of cellular derangement that results in rampant cell proliferation and failure of defective cells to commit suicide.  Aberrant activation of Wnt signaling is strongly implicated in cancers such as non-small cell lung cancer (NSCLC, the most common type of lung cancer), mesothelioma, and esophageal, colorectal, and nasal‑pharyngeal carcinomas.  For the past nine years, the Thoracic Oncology Laboratory has intensely investigated the role of the Wnt signaling pathway in cancers that afflict the majority of patients in the Thoracic Oncology Clinic.

Integral to our translational ("benchtop-to-bedside") focus is the development of novel therapeutic agents targeting Wnt signaling. The Disheveled (Dvl) molecule, a key mediator of Wnt signaling and one the lab has shown to be overexpressed in NSCLC, is another key target.  When downregulated, Dvl appears to inhibit cell proliferation and selectively induce apoptosis in lung cancer.  Wnt activation appears to be mediated by PDZ domain interactions between Dvl and Frizzled (Frz) proteins, and it is believed that inhibiting these interactions in cancers overexpressing Dvl will prove an attractive targeted therapy strategy in NSCLC patients.  As such, the lab is developing an assay to inhibit PDZ domain interactions between Dvl and Frz proteins.

Previously, research in the Thoracic Oncology Laboratory demonstrated that hypermethylation silencing in the promoter region of two natural Wnt antagonists, Secreted Frizzled Related Protein (sFRP) and Wnt Inhibitory Factor 1 (WIF-1), is associated with aberrant Wnt pathway activation.  Conversely, functional restoration of sFRP and WIF-1 selectively induces apoptosis and suppresses tumor growth in cell lines associated with cancers of interest.  The working hypothesis is that the methylation status of Wnt antagonists could serve as a diagnostic marker for cancer, and the presence of such silenced antagonists in collections of tumor specimens obtained through the Thoracic Oncology Program is therefore being evaluated. The lab is also evaluating the anti-tumorigenic effects of recombinant WIF‑1 proteins in vitro and in mouse xenograft models of human cancer.