Centre de Référence Maladies Rares

U1035 INSERM

Biotherapy of genetic diseases, inflammatory disorders and cancers (BMGIC)

FR: Biologie Fondamentale Appliquée à la Médecine

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MIRCADE team (Methods and Innovations for Research in Pediatric Cancers)
Project 5.2

Brain : diffuse intrinsic pontine gliomas, DIPG

keywords: diffuse intrinsic pontine gliomas, DIPG, chick chorioallantoic membrane

Description:

Principal investigator : M. Hagedorn, MD, PhD, Assist. Prof.
Workgroup members : C. Capdevielle, PhD student; F. Rahal, PhD student; J. Charpentier, Assist. Engineer.

This project focuses on the molecular and preclinical study of DIPG, the deadliest pediatric brain tumor. We have recently identified two pro-tumoral proteins induced by the HDAC inhibitor Panobinostat. We are currently evaluating a novel anti-tumor strategy by blocking one of these proteins together with panobinostat treatment. A novel research project aims to shed light on a novel oncogene selectively expressed during embryogenesis in the developing pons and overexpressed in these tumors.

Last article in Neuro-Oncology at this link
Abstract
Diffuse midline glioma (DMG) is a pediatric malignancy with poor prognosis. Most children die less than one year after diagnosis. Recently, mutations in histone H3 have been identified and are believed to be oncogenic drivers. Targeting this epigenetic abnormality using histone deacetylase (HDAC) inhibitors such as panobinostat (PS) is therefore a novel therapeutic option currently evaluated in clinical trials.
Methods : BH3 profiling revealed engagement in an irreversible apoptotic process of glioma cells exposed to PS confirmed by annexin-V/propidium iodide staining. Using proteomic analysis of 3 DMG cell lines, we identified 2 proteins deregulated after PS treatment. We investigated biological effects of their downregulation by silencing RNA but also combinatory effects with PS treatment in vitro and in vivo using a chick embryo DMG model. Electron microscopy was used to validate protein localization.
Results : Scaffolding proteins EBP50 and IRSp53 were upregulated by PS treatment. Reduction of these proteins in DMG cell lines leads to blockade of proliferation and migration, invasion, and an increase of apoptosis. EBP50 was found to be expressed in cytoplasm and nucleus in DMG cells, confirming known oncogenic locations of the protein. Treatment of glioma cells with PS together with genetic or chemical inhibition of EBP50 leads to more effective reduction of cell growth in vitro and in vivo. Our data reveal a specific relation between HDAC inhibitors and scaffolding protein deregulation which might have a potential for therapeutic intervention for cancer treatment.

Related publications:

  • HDAC inhibition induces expression of scaffolding proteins critical for tumor progression in pediatric glioma: focus on EBP50 and IRSp53 C. Capdevielle, A. Desplat, J. Charpentier, F. Saggliocco, P. Thiebaud, N. Thézé, S. Fédou, K. B Hooks, R. Silvestri, V. Guyonnet-Duperat, M.Pretel, A.A. Raymond, J.W. Dupuy, C. F Grosset, M. Hagedorn Neuro-Oncology () doi: 10.1093/neuonc/noz215
  • Accessing key steps of human tumor progression in vivo by using an avian embryo model. Hagedorn M1, Javerzat S, Gilges D, Meyre A, de Lafarge B, Eichmann A, Bikfalvi A. PNAS () PMC547849

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INSERM U1035 - University of Bordeaux
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sarah.lesjean@inserm.fr