Role of Fibroblast-Growth Factor Signalling in Epithelial Remodelling
Lead Research Organisation:
University of Dundee
Department Name: College of Life Sciences
Abstract
Our body is composed of different organs and tissues, which all work together to deliver the functions that identify us as healthy human beings. The major types of tissues in our body are sheet-like assemblies of cells, called epithelia. Epithelia have a top and a bottom side. The top or apical side faces the outside world (skin) or the lumen of an organ (gut, glands, kidney) and the bottom or basal side faces the inside of the organism. This polarized architecture is essential for the function of epithelia. For example a disruption of the gut epithelium will impair uptake of nutrients and eventually cause inflammation. Loss of epithelial polarity can also cause diseases such as fibrosis, where excessive connective tissue is formed. Moreover, loss of epithelial polarity is a key event in the dissemination of cancer cells into different parts of the body, a process called metastasis.
The mechanisms that cancer cells utilize to become malignant are often recapitulations of events that normally occur during embryogenesis. During development a primitive embryonic epithelium is formed that partially undergoes a conversion to non-epithelial (mesenchymal) cells. These mesenchymal cells develop further into muscles, heart and blood cells. Improper cell movements during these stages of development can result in abortive development and congenital defects in animals and humans.
Our research project addresses the question how cell signalling can elicit the transition of an epithelial cell to a mesenchymal cell (called EMT). Our laboratory will utilize genetics to identify molecules important for epithelial cells to loose their epithelial polarity in EMT. Research on human embryos is highly problematic for obvious ethical reasons. Modern biomedical research uses model organisms to study basic biological mechanisms because these are often very similar in different organisms. For example the principle genes that control cell division are quite similar from yeast to man. We utilize the fruit fly as a model system to find genes that are involved in EMT. The principal molecules that control the development of the fly are also critical for the development of human embryos. This finding was awarded the Nobel Prize for Medicine in 1995. Furthermore, more than 75% of all genes that have been identified to cause diseases in humans are also present in the fly. Therefore the fly is an excellent system to perform detailed research which findings can eventually be translated from the basic research laboratory to the clinic.
The mechanisms that cancer cells utilize to become malignant are often recapitulations of events that normally occur during embryogenesis. During development a primitive embryonic epithelium is formed that partially undergoes a conversion to non-epithelial (mesenchymal) cells. These mesenchymal cells develop further into muscles, heart and blood cells. Improper cell movements during these stages of development can result in abortive development and congenital defects in animals and humans.
Our research project addresses the question how cell signalling can elicit the transition of an epithelial cell to a mesenchymal cell (called EMT). Our laboratory will utilize genetics to identify molecules important for epithelial cells to loose their epithelial polarity in EMT. Research on human embryos is highly problematic for obvious ethical reasons. Modern biomedical research uses model organisms to study basic biological mechanisms because these are often very similar in different organisms. For example the principle genes that control cell division are quite similar from yeast to man. We utilize the fruit fly as a model system to find genes that are involved in EMT. The principal molecules that control the development of the fly are also critical for the development of human embryos. This finding was awarded the Nobel Prize for Medicine in 1995. Furthermore, more than 75% of all genes that have been identified to cause diseases in humans are also present in the fly. Therefore the fly is an excellent system to perform detailed research which findings can eventually be translated from the basic research laboratory to the clinic.
Technical Summary
Epithelial cells develop a highly polarized cyto-architecture evident by a polarized cell surface and cytoskeletal organization. Although epithelial cells are differentiated cells, they maintain a high degree of plasticity that allows them to react upon injury and invasion, to undergo morphogenesis and to maintain tissue homeostasis. This plasticity requires that the polarized architecture of epithelial cells is flexible and that the cells are able to remodel the junctional cell adhesive properties between each other. The most radical epithelial remodelling occurs during epithelial-mesenchymal transitions (EMT) were epithelial polarity is completely abrogated eventually.
A key event in EMT is the loss of apical-basal polarity and remodelling of epithelial adherens junctions. Transcriptional down regulation of E-cadherin by Snail family and other transcription factors plays a major role in EMT and is in some cases sufficient for EMT of cultured epithelial cells. These observations led to a widely accepted point of view in the field that EMT describes the transition of epithelial cells to mesenchymal cells by transcriptional down-regulation of epithelial genes, most notably E-cadherin and up-regulation of mesenchymal genes.
However many examples have shown that transcriptional regulation of E-cadherin cannot alone be responsible for EMT. In many cases during development and metastasis, E-cadherin is still present on cells that undergo EMT. As these processes might escape the commonly accepted definition of EMT, we consider these processes as epithelial remodelling as the cells maintain some epithelial properties but have lost apical-basal polarity. The regulation of this process is poorly understood.
We address the problem of epithelial remodelling using Drosophila embryos. Drosophila represents an excellent system for this research, because the major players are conserved (Twist, Snail, E-cadherin, PAR complex, FGF8), the organization of the embryo is simple and the cells are relatively large and easy to image. The objective of the proposal is to determine the control of epithelial remodelling in gastrulation.
The aims are:
- To determine the temporal-spatial control of core polarity components during epithelial remodelling
- To determine the contribution and hierarchy of Twist, Snail and FGF signalling in epithelial remodelling
- To determine the mechanism of DE-cadherin regulation by FGF signalling
The results of this research are aimed at a better understanding of the mechanisms that control the plasticity of epithelial cells. In particular the results will be of relevance for the research on E-cadherin-positive malignant cancers and the possible involvement of FGF signalling in their propagation.
A key event in EMT is the loss of apical-basal polarity and remodelling of epithelial adherens junctions. Transcriptional down regulation of E-cadherin by Snail family and other transcription factors plays a major role in EMT and is in some cases sufficient for EMT of cultured epithelial cells. These observations led to a widely accepted point of view in the field that EMT describes the transition of epithelial cells to mesenchymal cells by transcriptional down-regulation of epithelial genes, most notably E-cadherin and up-regulation of mesenchymal genes.
However many examples have shown that transcriptional regulation of E-cadherin cannot alone be responsible for EMT. In many cases during development and metastasis, E-cadherin is still present on cells that undergo EMT. As these processes might escape the commonly accepted definition of EMT, we consider these processes as epithelial remodelling as the cells maintain some epithelial properties but have lost apical-basal polarity. The regulation of this process is poorly understood.
We address the problem of epithelial remodelling using Drosophila embryos. Drosophila represents an excellent system for this research, because the major players are conserved (Twist, Snail, E-cadherin, PAR complex, FGF8), the organization of the embryo is simple and the cells are relatively large and easy to image. The objective of the proposal is to determine the control of epithelial remodelling in gastrulation.
The aims are:
- To determine the temporal-spatial control of core polarity components during epithelial remodelling
- To determine the contribution and hierarchy of Twist, Snail and FGF signalling in epithelial remodelling
- To determine the mechanism of DE-cadherin regulation by FGF signalling
The results of this research are aimed at a better understanding of the mechanisms that control the plasticity of epithelial cells. In particular the results will be of relevance for the research on E-cadherin-positive malignant cancers and the possible involvement of FGF signalling in their propagation.
Organisations
People |
ORCID iD |
| Arno Muller (Principal Investigator) |