Modulation of epithelial-to-mesenchymal transition (EMT) with small molecules

EMT is a widespread and important biological process that relies on a genetically induced reduction of coordinated cell behavior. This reduction allows individual cells inside an epithelium to change their properties (i.e. enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and increased production of extracellular matrix components) and leave it as individual, mesenchymal cells. Understanding the regulation of cell behavior during EMT is crucial for understanding core developmental processes like muscle and heart development, and it has recently become a focus in the investigation of new strategies against cancer and cancer resistance.

The Lemke lab has identified two extreme modes of EMT-related processes in the midge C. riparius and the fruit fly D. melanogaster. In Chironomus, levels of cell coordination were low: future muscle cells leave the epithelium and translocate to the inside of the embryo using canonical EMT. In Drosophila, levels of cell coordination were high and EMT was delayed: cells remained in an epithelium, collectively folded into the inside of the embryo, and only then gradually separated. Genetic investigations have shown that two genes act as a switch to evoke canonical EMT in Drosophila, and delayed EMT in Chironomus, rendering this pair of species as an in vivo test tube to reveal factors that are necessary and/or sufficient to strengthen epithelial integrity and suppress EMT. To identify factors beyond the known genetic players, we will identify and investigate small molecules that trigger changes in cell and tissue behavior. The initial compounds will be obtained by natural product isolation and selection of promising core structures from the ComPlat library. By comparing genetic with compound-induced changes, the mechanism of EMT suppression will be further dissected. More generally, we aim to identify previously proposed but still unknown biological targets that regulate the coordination of cell behavior.

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