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Notch and epithelial proliferation

Final Report Summary - PRONO (Notch and epithelial proliferation)

During development, the different organs and tissues of an organism have to grow harmoniously to reach their specific shapes and sizes. In the adult, organs have usually reached an equilibrium, where loss of cells must be compensated by tightly regulated proliferation. During cancer, groups of cells evade these controls and start to proliferate abnormally.

The Notch intercellular signalling pathway is very conserved throughout evolution and directs a wide variety of cell fate decisions and behaviours. The specificity of outcome relies on the implementation of different transcriptional programmes. Upon activation, the receptor Notch will translocate into the nucleus of cells where after binding with the Su(H)/CSL/RBPJ transcription factors, it will direct the expression of specific target genes, governing proliferation, cell survival, cell determination... For instance, depending on cancer type, Notch signalling can act either as a tumour suppressor (anti-proliferative; bladder or head and neck cancers for instance), or as an oncogene (pro-proliferative; T-cell leukemias and non-small cell lung cancers). Apart from the role of Notch inferred from its mis-regulations in many cancers, Notch controls epithelial cell proliferation and tissue growth in many epithelia from very diverse animals, in particular the developing wing in Drosophila.

The project PRONO (618371) on Notch and epithelial proliferation seeks to better understand how Notch controls epithelial cell proliferation in the animal model Drosophila, in particular at the level of the intricate regulations of the gene network activated downstream of Notch. The knowledge acquired will shed light onto how mis-regulations of Notch or changes in the architecture of its gene network could lead to uncontrolled tissue growth and cancers.

Through the implementation of genomic approaches and functional validation in the developing animal we have:
- described the contribution of the microRNAs (miRs) in shaping the Notch transcriptional network activated during Notch mediated hyperplastic epithelial growth in Drosophila wing discs, uncovering many incoherent feed-forward loops.
- explored how changes in cell architecture influence the Notch signalling pathway.
- performed a detailed functional analysis of a new Notch target part of a macromolecular complex affecting cell architecture and shown that it fine-tunes the activity of the major anti-proliferative Hippo pathway.

Finally, it should be highlighted that thanks to the support of this CIG Marie Curie, I have been able to set-up an independent research team in an expanding interdisciplinary institute dedicated to cancer research, and to attract talented scientists to join the team. The PRONO project will have long-lasting effects, since it led the team to accumulate unique data and expertise on new Notch direct target genes potentially affecting proliferation and cell adhesion which we will functionally characterise in the future.