7th Annual Symposium
Physics of Cancer
October 4-6, 2016
|PoC - Physics of Cancer - Annual Symposium|
Basement Membrane Fragments Contribute to the Regulation of the Epithelial-to-Mesenchymal Transition
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 2, Stockholm, 17177, Sweden
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The epithelial-to-mesenchymal transition (EMT) enables cells of epithelial phenotype to become motile and change to a migratory mesenchymal phenotype. EMT is known to be a fundamental requisite for tissue morphogenesis, and EMT-related pathways have been described in cancer metastasis and tissue fibrosis. Epithelial cells deposit a sheet-like extracellular matrix, the basement membrane, which is assembled from two major proteins, laminin and collagen type IV. This specialized matrix is essential for tissue function and integrity, and provides an important barrier to the potential pathogenic migration of cells. The profound phenotypic transition in EMT involves the proteolytic breakdown of the basement membrane. Matrix metalloproteinases (MMPs) are known to cleave components of basement membranes and a variety of basement membrane fragments have been shown to be released by specific MMPs in vitro and in vivo exhibiting distinct biological activities.
We have recently reported a previously unidentified laminin fragment that is released during EMT by MMP2 and that modulates key EMT-signaling pathways. Specifically, interaction of the laminin fragment with α3β1-integrin triggers the down-regulation of MMP2 expression and a decrease in cell migration, thereby constituting a cell-matrix-cell feedback mechanism that contributes to the regulation of EMT and MMP activity. We explored this feedback mechanism to target pathological EMT in vivo, and developed an electrospun synthetic membrane that is functionalized with the recombinant laminin fragment and that can be directly interfaced with epithelial tissue to interfere with EMT pathways and inhibit MMP2 expression. Interaction of the functionalized synthetic membrane with peritoneal tissue inhibits TGFβ1-induced mesothelial EMT in vivo by decreasing active MMP2 levels and therefore, preventing basement membrane breakdown. Specifically, the functionalized synthetic membrane triggers changes in EMT-related transcription factor expression and nuclear translocation through the specific interaction of the laminin fragment with α3-integrin, suggesting a novel mechanism of how the basement membrane is involved in EMT regulation.