BBB seminar: Ulrich Valcourt
Tenascin-X promotes epithelial-to-mesenchymal transition by activating latent TGF-β
Cancer Research Center of Lyon (CRCL), French Institute of Health and Medical Research (INSERM), University of Lyon, France
In our laboratory, we are interested in the role of Transforming Growth Factor-β (TGF-β) in pancreatic cancers. TGF-β isoforms are secreted as inactive complexes formed through noncovalent interactions between the bioactive TGF-β entity and its N-terminal propeptide (LAP). Latent TGF-β can be found as a soluble entity, called the small latent complex, but it is also secreted as a large latent complex that is sequestered in the extracellular matrix. In some physiological or pathological contexts, mature TGF-β is released from the latent complex, a process called latent TGF-β activation. Extracellular activation of the latent TGF-β complex is a crucial step in the regulation of TGF-β function for tissue homeostasis. In the laboratory, we work on Tenascin-X, a trimeric extracellular matrix glycoprotein of 450 kDa displaying a modular structure. We showed that the C-terminal fibrinogen-like (FBG-like) domain of Tenascin-X interacted physically with the small latent TGF-b complex in vitro and in vivo. We also provided evidence that the FBG-like domain couldregulate the bioavailability of mature TGF-β to cells by activating the latent cytokine into a bioactive molecule. We demonstrated that the activation by the FBG-like domain most likely occurred through a conformational change in the latent complex and involved a novel cell-adhesion-dependent mechanism. We identified α11β1 integrin as a cell surface receptor for Tenascin-X and showed that this integrin was crucial to eliciting FBG-like domain mediated activation of latent TGF-β and subsequent epithelial-to-mesenchymal transition in mammary epithelial cells. We are currently investigating the biological relevance of latent TGF-β activation by Tenascin-X in vivo by analyzing the TGF-β signaling in Tenascin-X-deficient mice in normal conditions and during pancreatic cancer progression.
Chairperson: Donald Gullberg, Department of Biomedicine