Int. J. Dev. Biol. In Press
doi: 10.1387/ijdb.210187cd
© UPV/EHU Press

Repression of differentiation genes by Hes transcription factors fuels neural tumour growth in Drosophila

Chrysanthi Voutyraki1,2, Alexandros Choromidis1,2, Vasiliki Theodorou1, Christina Efraimoglou1,2,3, Gerasimos Anagnostopoulos1,2,4,5,6, Srivathsa S Magadi1,2,7, Sofia Grammenoudi8, Evanthia Zacharioudaki*,1 Christos Delidakis*,1,2

1Institute of Molecular Biology and Biotechnology, Foundation for Research & Technology Hellas, Heraklion, Crete, Greece, 2Department of Biology, University of Crete, Heraklion, Crete, Greece, 3Institute for Genome Stability in Ageing and Disease, Medical Faculty and Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases, Center for Molecular Medicine Cologne, University of Cologne, Germany, 4Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France, 5Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France, 6Faculté de Médecine, Université de Paris Saclay, Kremlin Bicêtre, France, 7Department of Biomedical and Clinical Sciences, Wallenberg Center for Molecular Medicine, Linköping University, Linköping, Sweden and 8Institute for Fundamental Biomedical Research, BSRC Alexander Fleming, Vari, Greece

ABSTRACT

Background: Neural stem cells (NSC) in divide asymmetrically to generate a cell that retains stem cell identity and another that is routed to differentiation. Prolonged mitotic activity of the NSCs gives rise to the plethora of neurons and glial cells that wire the brain and nerve cord. Genetic insults, such as excess of Notch signaling, perturb the normal NSC proliferation programs and trigger the formation of NSC hyperplasias, that can later progress to malignancies. Hes proteins are crucial mediators of Notch signaling and in the NSC context they act by repressing a cohort of early pro-differentiation transcription factors. Downregulation of these pro-differentiation factors makes NSC progeny cells susceptible to adopting an aberrant stem cell program. We have recently shown that Hes overexpression in Drosophila leads to NSC hyperplasias that progress to malignant tumours after allografting to adult hosts.

Methods: We have combined genetic analysis, tissue allografting and transcriptomic approaches to address the role of Hes genes in NSC malignant transformation.

Results: We show that the E(spl) genes are important mediators in the progression of Notch hyperplasias to malignancy, since allografts lacking the E(spl) genes grow much slower. We further present RNA profiling of Hes-induced tumours at two different stages after allografting. We find that the same cohort of differentiation-promoting transcription factors that are repressed in the primary hyperplasias continue to be downregulated after transplantation. This is accompanied by an upregulation of stress-response genes and metabolic reprogramming.

Conclusions: The combination of dedifferentiation and cell physiology changes most likely drive tumour growth.

Keywords:

neural stem cells, CNS tumour, Hes proteins, Notch, Drosophila

*Corresponding author e-mail: delidaki@imbb.forth.gr ; evanthia_zacharioudaki@imbb.forth.gr