The Epithelial-Mesenchymal Transition in Cancer and Metastasis
Thursday, January 24, 2008
Presented by Cancer and Signaling Discussion Group
Organizers: David Epstein and John Haley, OSI Pharmaceuticals, Inc.
Tumor transition to a more mesenchymal-like state plays a major role in the progression of cancer, and the acquisition of a mesenchymal phenotype has been linked to poor prognosis. Attend an interactive discussion on recent data highlighting the conversion of epithelial cancer cells to a more mesenchymal-like state, a process termed epithelial-mesenchymal transition (EMT), to facilitate cell invasion and metastasis.
Meetings of the Cancer and Signaling Discussion Group focus on specific themes as they relate to signal transduction dysregulation in oncogenesis and will cover basic, clinical, and diagnostic aspects of the field.
New Insights Into EMT From Genetics and Live-Cell Imaging
Denise Montell, PhD
Johns Hopkins University School of Medicine
In both normal embryonic development and in a variety of pathological conditions, epithelial cells can acquire migratory and invasive properties, a transformation that invariably requires alterations in gene expression. For cells to leave an epithelium, it is necessary to distinguish the migratory cells from those that will remain behind and for these two cell types to detach from one another. Border cells in the Drosophila ovary serve as a genetically tractable model for elucidating the molecular mechanisms that control such behaviors. Recently we have defined conditions that allow us also to make time-lapse films of the process in living organ culture. We have found that the initial steps of migration are much slower than expected and that extraction of the cells from the epithelium is a rate-limiting step. Several new mutants we have identified affect this step. In addition we find that in vivo, guidance receptor activity does not stimulate cell protrusion. Rather, the cells are constitutively protrusive and guidance receptor activity provides cell polarity that determines the direction of cell protrusion and migration. The role of the cell polarity protein Par-1 in border cell migration will be presented.
Tumor-Induced Angiogenesis: Dissecting The Molecular Mechanism Controlling Endothelial Cell Permeability
Julie Gavard and J. Silvio Gutkind,
National Institute of Dental and Craniofacial Research
To investigate the molecular mechanism underlying the vascular leakiness that characterizes tumor vessels, we studied how VEGF, a potent angiogenic factor, causes endothelial permeability. We observed that VEGF acts on its receptor, VEGFR2, to initiate the activation of a signaling axis that involves Src, Vav2, Rac, and Pak. This results in the phosphorylation of the intracellular tail of a key endothelial cell adhesion molecule, VE-cadherin, thereby promoting its internalization and the consequent disassembly of endothelial adherens junctions. This novel biochemical route may help identify new targets for pharmacological intervention in many human diseases that involve pathological vascular leakage, including cancer.
MicroRNAs and Gene Regulation in EMT
Jiri Zavadil, PhD
New York University School of Medicine
We present EMT-specific microRNA signature harboring oncogenic microRNAs, elevated in tumors and during fibrogenesis. The promoter of the top microRNA binds Smad complexes, potentially conveying the oncogenic effects of TGF-β in EMT. The candidate microRNA is predicted to target tumor suppressor genes and to drive EMT through ECM degradation by inhibiting a TIMP gene. A CpG island hyper-methylation of the TIMP promoter was observed in cells from advanced tumors including breast cancer cell lines. The significance of a model integrating cell signaling, transcription activation of microRNAs and epigenetic silencing of tumor suppressor genes in carcinoma progression will be discussed.