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Molecular Basis of Cancer Progression and Metastasis
Pancreatic cancer is one of the most lethal forms of human cancer, with five-year survival at less than five percent. Due to lack of effective methods for early detection and treatment, most cases are not diagnosed until the disease has reached the advanced stage, when the cancer has disseminated to a distant site, such as the liver. The signaling interactions between cancer cells and stromal cells are thought to play a pivotal role in promoting neoplastic transformation. Recent work in the Wang Laboratory has led to identification of novel biomarkers for pancreatic cancer progression. These include elements of the MSP-RON and Hippo-YAP signaling pathways. We are now using both genetic and proteomic approaches to decipher the signaling events important for driving malignant transformation in the pancreas. The Wang Laboratory has also developed a mouse model to examine how pancreatic cancer cells survive and cause remodeling of the host environment to their favor upon dissemination to the liver.
Pancreatic Tissue Regeneration and Alcoholic Pancreatitis
Chronic pancreatitis is a painful and, sometimes, lethal disease characterized by long-term tissue injury and inflammation of the pancreas, and is linked with increased incidence of pancreatic cancer. Alcohol abuse is a leading risk factor for chronic pancreatitis; however, the molecular mechanism involved is not well understood. A Wang Laboratory recent study indicates that the YAP signaling pathway may play a role in pancreatic tissue regeneration and in pathogenesis of pancreatic diseases, such as pancreatic cancer and pancreatitis. YAP levels are drastically elevated in activated stellate cells, the myofibroblast-like cells that play a defining role in tissue inflammation and fibrogenesis in pancreatitis. Current work in the Wang Lab is focused on investigating the role of YAP in stellate cell function and tissue regeneration, and whether deregulation of YAP promotes the inflammatory microenvironment in alcohol-associated pancreatitis.
Cancer Drug Resistance and Targeted Therapy
The ErbB receptors, such as EGFR and HER2, contribute to breast, ovarian and lung cancer development. Although drugs targeting the ErbB molecules have been used clinically with some success, a major problem is that many patients who are initially responsive to ErbB-targeted therapies experience recurrence and become refractory to the therapies. Recent studies in the Wang Laboratory indicate that abnormalities of survivn-mediated mitotic checkpoint, as well the Hippo-YAP signaling pathway, may render cancer cells resistance to a variety of cancer therapeutics. We have also identified novel regulatory elements of the Hippo-YAP signaling pathway. YAP activation is associated with malignant transformation and cancer stem cell phenotype. Understanding the functional interactions between the ErbB and Hippo-YAP pathways may provide insights into new therapeutic opportunities for the treatment of human cancers.
Cell Cycle Regulation
The Wang Laboratory is interested in mechanisms involved in maintaining genetic integrity. We use cell and molecular biology approaches to identify and characterize key regulators of the processes of mitosis, centrosome duplication and DNA damage repair. Members of the Wang Lab are developing new cancer therapeutics that target these regulatory molecules, including survivin, which is over expressed in a variety of human cancers. Our ongoing work is to demonstrate the proof-of-principle that targeting survivin can be used as a strategy to treat human malignancy. We are also investigating the role of SUN domain-containing proteins in DNA damage response and tumorigenesis. The Wang Lab has solved the crystal structure of the SUN domain of the human SUN2 protein, which provides the molecular basis for further understanding the biological functions of the SUN2 complex.