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Effects of 3D topographies on mechanosensing in intestine epithelial architecture and dynamics

Project description

Molecular players in intestinal epithelial topography

The epithelium is a widespread tissue that covers all the outer and inner surfaces of our body including the skin and the intestine. Apart from its role as a physical barrier, the intestinal epithelium serves to regulate nutrient uptake and interacts with microbiota. However, little is known regarding the mechanisms that determine its architecture and dynamics. The EU-funded TOPOGRAPHYSENSING project is examining the role of the epithelial cell adhesion molecule (EpCAM), a transmembrane glycoprotein. Researchers will assess how EpCAM senses mechanical cues from the microenvironment to drive the spatial organisation of epithelial cells in the intestine.


Intestine epithelium consists of spatially segregated cells that organize into groups of various functions at different locations
of the 3D curved epithelial monolayer. How geometric cues contribute to the maintenance of the sophisticated epithelial architecture and dynamics in 3D remains unknown until now. Recently, the Ladoux's laboratory has found that EpCAM-modulated cell contractility associated with the epithelial monolayer polarity, cytoskeletal arrangement, and cell-cell adhesion in 3D context. In contrast to 2D context, the EpCAM-defective tissue shows a loss of collective cellular spatial organization and forms a disordered multi-layered epithelium when exposed to substrates of 3D topographies. In addition, Ankyrin-G and α/β-spectrin network which participates in cortical tension modulation was identified as the main interacting partner with EpCAM in epithelial cells. These observations lead us to hypothesize that EpCAM allows the tissue to sense and conform to complex 3D topographies in an orderly manner. However, the molecular mechanisms and other related functions of EpCAM-mediated mechanotransduction remain unknown. As large scale mechanosensing has been shown to occur primarily through the actin cytoskeleton which permeates the tissue to form a network, we aim to understand the interactions between the EpCAM-mediated pathway and actin modulation and/or E-cadherin adhesion sites that may allow 3D topographical sensing. Our working hypothesis is that EpCAM forms an integral part of the cellular responses to topographic cues that has a more general role in controlling epithelial architecture and dynamics through the regulation of actomyosin networks, or vice versa. Here, we propose to scrutinize EpCAM-mediated mechanotransduction by generating a platform with precise control of geometric factors and microenvironmental cues using a range of multidisciplinary approaches including microfabrication, biophysics, and advanced molecular biology techniques.


Net EU contribution
€ 134 600,08
Other funding
€ 62 107,76