Epithelial morphogenesis and cell polarity

"Epithelial cell polarity specification and maintenance is a key problem in cell biology. The vast majority of cancers in human originate from epithelia (i.e. Breast, Colon, Lung, Kidney, etc.) and a major hallmark of tumourogenesis is a progressive loss of epithelial cell polarity. We are studying this problem using the fruit fly Drosophila melanogaster, coming with an unparalleled genetic toolbox, and thus allowing us to manipulate the function of virtually every single gene present in its genome. While up to 80% of the genes associated with diseases in human are conserved in Drosophila, they are often present as one single gene, which is ideal to study a gene function, as very little redundancy is present. Using this approach, we are making significant progresses toward characterizing the molecular basis for establishing and maintaining epithelial cell polarity. This is particularly relevant for better tackling the process of tumorogenesis and metastasis, as these are characterized by a loss of epithelial cell polarity."

"The regulation of Epithelial cell polarity specification and maintenance is a key problem in cell biology. The vast majority of cancers in human originate from epithelia (i.e. Breast, Colon, Lung, Kidney etc.) and a major hallmark of tumourogenesis is a progressive loss of epithelial cell polarity. This eventually leads to Epithelial to Mesenchymal (EMT) cell transition a key step toward cell metastasis activity. Epithelial cell specification presents the converse step (i.e. Mesenchymal to Epithelial transition, MET). Better understanding the molecular mechanisms and signalling pathways required for promoting MET is therefore a key step toward a better understanding of EMT.||To tackle this question in vivo, we are using the genetically amenable Drosophila melanogaster. While up to 80% of the genes associated with diseases in human, are conserved in Drosophila, they are often present as one single locus, which is ideal as very little redundancy is present. So far this approach has allowed us to characterize the function of the conserved tumour suppressor PTEN, during epithelial apical membrane morphogenesis. PTEN is mutated in more than 50% of cancers in human. In epithelial cells, PTEN is recruited at the developing zonula adherens (za) through direct binding to the conserved polarity gene Par3/Baz. Our work in Drosophila has now been confirmed and validated in mammalian epithelial cells, by two other independent groups. Since then, we have tried to better characterize the PTEN/Par3 interface and in particular we have focussed our work on the problem of za morphogenesis and maintenance. The za is the principal membrane domain for the cells to form an epithelial sheet, as this domain is responsible for cell-cell anchorage. We believe that we have now solved a number of key open questions in this field of research. In particular, we have recently solved the molecular basis for Par3 requirement during za assembly in epithelial cells. Par3 and PTEN are also key genes for directed cell migration and we propose that in pathological conditions such as cancer, defect in their regulation in epithelial cells (i.e. phosphorylations/localization), and are likely to have a profound impact toward cell metastasis."