Major Research Interests
Dr. Chen’s laboratory focuses on the role of cellular signaling pathways in the differentiation and growth of neuroendocrine (NE) tumors including carcinoid, pancreatic islet cell, pheochromocytoma, and medullary thyroid cancer.
NE tumors are the second most common cause of isolated hepatic metastases. These tumors often cause debilitating symptoms due to excessive hormonal secretion which characterize these NE lesions. Besides surgery, there are limited curative and palliative treatments available to patients with NE tumors, emphasizing the need for development of other forms of therapy. Dr. Chen’s group has shown that activation of the ras/raf-1/MAP kinase signal transduction pathway, in human NE cells markedly suppresses cellular growth and causes changes in cellular morphology and adhesion in vitro. Moreover, over-expression of raf-1 also leads to a dramatic reduction in NE marker expression in human NE cells in vitro. Furthermore, in a mouse model of NE tumor progression, activation of raf-1 inhibited NE tumor growth and prevented liver metastasis. Their current research focuses on defining the mechanisms by which raf-1 exerts these effects. Their ultimate objective is to determine if modulation of the raf-1 signal transduction pathway could play a potential role in the management of patients with NE tumors, by modulating hormone secretion and growth. To this end they have identified several novel raf-1 activating compounds which modulate NE cancer growth.
Another focus in Dr. Chen’s lab involves the Notch1 signaling pathway. Notch1 is a multi-functional transmembrane receptor that plays an important role in cellular differentiation in the gastrointestinal (GI) tract. Similar to its role in developing nervous tissues, Notch1 signaling is thought to mediate a process called lateral inhibition within the GI tract. During GI development, multipotent cells destined to differentiate into enteroendocrine cells express the Notch1 ligand, Delta. Delta then binds to Notch1 receptors on neighboring undifferentiated cells. This triggers activation of Notch1 within the undifferentiated cells, leading to a cascade that inhibits the expression of pro-endocrine genes. Thus, the overall effect is to limit the number of cells which can differentiate into enteroendocrine cells. Dr. Chen’s lab has recently shown that over expression of Notch1 in GI carcinoid cells as well as in medullary thyroid cancer cells causes a dramatic reduction in hormone production accompanied by growth suppression. His group is currently developing animal models of GI carcinoid and medullary thyroid tumor progression to investigate the possible role of Notch1 in suppressing hormone production by these tumors. Dr Chen’s group is also initiating clinical trails with Notch1 activating compounds.
Additional Research Activities
In addition to his active laboratory effort, Dr. Chen has numerous clinical studies involving patients with parathyroid, thyroid, and adrenal disease. His clinical area of expertise is the role of minimally invasive endocrine surgery techniques in the management of patient with hyperparathyroidism, thyroid nodules, and adrenal lesions. He has a large experience with minimally invasive radioguided parathyroidectomy (MIRP). Currently, Dr. Chen has multiple ongoing, multi-disciplinary, prospective clinical trials. Links to these published clinical studies can be found at the University of Wisconsin thyroid, parathyroid and adrenal site.