Epithelial Plasticity and Epithelial to Mesenchymal Transition
Organizer(s): Rik Derynck, Harold A. Chapman and Raymond RunyanDate: January 21 - 26, 2011
Location: Fairmont Waterfront, Vancouver, BC, Canada
Epithelial-to-mesenchymal transition (EMT) is a basic cellular process in which epithelial cells lose epithelial properties, e.g. their polarized organization and cell-cell junctions, undergo changes in cytoskeleton and cell shape, acquire mesenchymal characteristics and become migratory and invasive. EMT was first recognized as distinct cell differentiation process in the late 70’s, and has received increasing attention, as it not only occurs in normal development but is also an integral component of various pathological conditions. An increasing understanding of the signaling and transcription processes that mediate EMT is starting to provide a framework of the underlying molecular mechanisms. During development, EMT occurs as early as gastrulation, when ectodermal cells give rise to mesoderm. In addition, embryonic stem cells in culture are epithelial in nature and, during colony formation, rapidly give rise to niche cells that lack epithelial characteristic and appear mesenchymal. EMT is reiterated at different stages and in different developmental contexts. Notably, neural crest cells delaminate and migrate to give rise to various mesenchymal cell populations. In addition, EMT occurs at distinct sites and stages in organogenesis, e.g. in the heart and pancreas. Conversely, mesenchymal to epithelial transition (MET) also occurs and may account for the reversal of cells that have undergone EMT back to the epithelial phenotype, illustrating the potential of EMT to be a transient and reversible process. Finally, it has become increasingly apparent that endothelial cells, similarly to epithelial cells, can lose endothelial characteristics and acquire mesenchymal properties. EMT has also been recognized as an important component of pathological conditions, and contributes to cancer progression, specifically invasion and metastasis of cancers, and fibrosis. While the contributions of EMT to cancer progression and fibrosis are debated, epithelial cells have been shown to undergo EMT in vivo under pathological conditions. In addition, in response to injury, epithelial cells reversibly lose epithelial characteristics and become migratory, illustrating the plasticity of the epithelial cells in wound healing. Studies on EMT have greatly benefited from the discovery that some growth and differentiation factors, most notably FGFs and HGF that act through receptor tyrosine kinases, and members of the TGF-beta family can induce EMT both in cell culture and in vivo, and from the establishment of cell culture models. These studies have provided great impetus to the dissection of signaling pathways that drive or contribute to EMT. Further, the identification of distinct families of transcription factors, whose expression is activated during EMT, allows a rapidly increasing insight into the transcription programs that drive EMT. Importantly, the signaling mechanisms and transcription programs that characterize EMT during development appear to be largely recapitulated during EMT processes under pathological conditions. Although EMT has been well documented during development, there is debate about its role and contribution in pathological conditions. The transient and reversible nature of EMT in cancer progression may contribute to some aspects of this debate, as cells that have undergone EMT may revert to their epithelial differentiation state and are therefore not easily identified. Another aspect of the debate centers around the acquisition of mesenchymal properties, especially since mesenchymal characteristics are ill-defined. Furthermore, in many cases epithelial cells lose epithelial characteristics and become migratory, but do not acquire mesenchymal marker expression. These observations suggest that a spectrum of epithelial plasticity changes can occur, resulting in downregulation of epithelial differentiation and integrity to different extents, and in changes that may or may not qualify as EMT. By considering EMT as the most striking manifestation of epithelial plasticity, much of the debate on the relative contribution of EMT to disease may be moot since different degrees of epithelial plasticity are observed. For example, while EMT has been implicated in cancer invasion, increased migration and invasion of cells with epithelial characteristics has also been documented as a basis for cancer invasion and progression. As another example, the changes in epithelial differentiation and organization of mammary epithelial cells during and following pregnancy and lactation also illustrate the inherent plasticity of epithelial cells that does not need to result in EMT. Further, during epithelial wound healing, different degrees of epithelial plasticity are observed. For example, striking plasticity is displayed by the airway respiratory epithelium following injury, where rapid conversion to a squamous phenotype protects the airway surface integrity, followed by reacquisition of multiple epithelial phenotypes during recovery. Finally, the realization that EMT provides a basis for cell invasion, leading to metastasis of carcinomas or fibrosis in different organs has also stimulated interest to find therapeutic modalities to inhibit EMT that consequently may interfere with or prevent the progression of metastases or fibrosis. In cancer, these considerations are energized by recent pre-clinical and clinical evidence that VEGF inhibitors as single agents promote invasion and metastasis, adversely affecting survival, and by preclinical results indicating that TGF-beta signaling inhibitors prevent or interfere with invasion and metastasis. Already, several recent clinical trials with antibodies and small molecules target signaling pathways known to drive EMT. Purpose of the Proposed Conference: We propose a conference roster to highlight the progress in our understanding of EMT against the background of the inherent plasticity of the epithelial cells. Following a keynote address, we propose a first session that will set the stage for subsequent sessions on EMT. This first session will discuss current insights into the differentiation of epithelial cells from stem cells, the maintenance of epithelial integrity and the inherent plasticity of epithelial cells. Against this background, the next seven sessions will discuss progress in our understanding of (1) the molecular mechanisms underlying epithelial plasticity and EMT (2 sessions), (2) the roles of EMT in normal development (2 sessions), (3) the roles of EMT in cancer (2 sessions) and fibrosis (1 session), including progress toward therapies based on inhibition of EMT. We appreciate that these divisions are artificial, since e.g. mechanistic studies are often validated in the context of development, cancer or fibrosis. Nevertheless, as artificial as these three subdivisions may be, we aim to give about equal weight to the cell biology of EMT, its developmental roles and its roles in pathology. The overall subject matter of the different aspects of the proposed conference is highlighted in the Background section above and in the discussion of the individual sessions further below, to which we refer. The purpose of this conference will be to bring together scientists who work on disparate aspects of epithelial plasticity and EMT. We expect to see an integration of cell and molecular biologists, developmental biologists, cancer biologists and organ/tissue biologists. Many of these scientists may be basic scientists, yet we also expect a substantial participation by scientists with translational interest and clinician-scientists, and significant interest from pharmaceutical and biotechnology industry.
Scholarship Deadline: September 21 2010
Discounted Abstract Deadline: September 21 2010
Abstract Deadline: October 25 2010
Discounted Registration Deadline: November 22 2010
We gratefully acknowledge additional in-kind support for this conference from those foregoing speaker expense reimbursements:
Astellas Pharma Inc.