The role of the cryptic basement membrane during the epithelial-to-mesenchymal transition

Abstract

The Extracellular Matrix (ECM) is a complex structure composed of proteins and polysaccharides that assemble into an organized network, which besides giving physical support to the cell, influences it main biological processes, such as cell survival, shape,polarity and behavior. This dynamic role is due to the presence of cryptic sites locatedin ECM proteins. A cryptic fragment of laminin-111 released by matrixmetallo proteinase 2 (MMP2) proteolytic activity was identified in Molly Stevens’ groupat Imperial College London. MMP2 cleaves the β1-chain of laminin-111, leading to the release of the β1–LN–LE1-4 fragment. Once released, it binds to α3-integrin in the cell membrane and modulates the epithelial-to-mesenchymal transition (EMT), an important process in development, tissue fibrosis and cancer metastasis. In tissue fibrosis, excess of scar tissue can be accumulated leading to inhibition of normal tissue functions. Since EMT is a crucial process in fibrosis, researchers proposed preventing epithelial cells to adopt mesenchymal features as a potential treatment strategy. In this work, the effect of this cryptic laminin fragment was evaluated in mus musculus mammary gland epithelial cells (NMuMGs) undergoing transforming growth factor β (TGFβ)-induced EMT using imaging and biochemical techniques. In this project, it is shown that the laminin β1-fragment down-regulates EMT-related markers in NMuMG cells, providing a potential reduction of fibrosis pathology. In future work, the relationship between different cellular pathways will have to be shown and possible application strategies to be developed. This project explores the tremendous potential of the information hidden within cryptic ECM sites.

Date of Award	30 Mar 2017
Original language	English
Awarding Institution	Universidade Católica Portuguesa
Supervisor	Christine-Marie Horejs (Supervisor) & Molly Stevens (Co-Supervisor)