Plasticité gliale et neuro-oncologie

Growth and resistance to therapy of high-grade glioma are thought to be dictated by glioma stem cells (GSC) that fuel the tumor and contribute to its recurrences. 

A relevant solution to target GSC is to force their exit from the stem state, and to prevent other tumor cells to acquire stem properties. In this context, we characterized GSC from adult and pediatric high-grade gliomas, and identified compounds toxic for GSC but without effect on human neural stem cells. 

We uncovered bi-directional interactions of GSC with their microenvironment, and micro-RNAs that trigger loss of their properties. Molecular profiling of GSC forced to exit the stem state revealed unexpected reprogramming in complex networks gathering metabolites, regulators of epigenetics and transcription factors. We currently focus on the functional consequences of these reprogramming on chromatin structure and subsequent GSC behavior, including their interaction with the environment. In parallel, we develop molecular tools to monitor in vivo changes in the cell functional states along tumor development.

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Our project aims at obtaining a comprehensive overview of the molecular pathways that favor or restrict the stem-like potential, and consequently the tumorigenicity of Glioma Stem Cells (GSC). Glioma are primary central nervous system tumors characterized by cell heterogeneity, variable clinical evolution of histologically similar tumors, and lack of detectable preneoplasic state.

Our finding that de-differentiated glial cells may behave as cells of origin of glioma suggested that cancer cells with stem- or progenitor–like properties could be a generic component of glioma, regardless of the mature or immature state of their cells of origin. Accordingly, a growing body of evidence indicates that cancer stem cells play a major role in determining the behavior of high-grade glioma, and their resistance to current therapies. We isolated and characterized at the molecular and functional levels GSC from adult and pediatric high-grade gliomas, and identified compounds that overcome their peculiar resistance to current therapies, whereas sparing human neural stem cells. Our studies of GSC response to environmental cues revealed bi-directional interactions with endothelial cells, and a novel angiogenic factor proper to GSC. They also uncovered a micro-RNA cluster miR-302-367 that commits GSC into a non stem-like state, and suppress their ability to initiate tumors.

We used the unique model offered by GSC and GSC-miR-302-367 to further explore the molecular networks sustaining GSC properties. With transcriptome and metabolome profiling, we uncovered an unexpected functional link between reprogramming of specific metabolic pathways, inhibition of the activity of enzymes ensuring epigenetic regulation of gene expression, and repression of GSC stem properties (Elias El-Habr, Luis G Dubois, Ashwin Narayanan). With genome-wide profiling of permissive and repressive histone marks (ChIP-Seq), and genetic manipulations we identified transcription factor networks necessary for maintenance of GSC stem properties (Alexandra Bogeas). Proteomic exploration of the secretome of the cells, confronted with transcriptome results pinpointed several proteins likely to facilitate the expansion of GSC within the brain. Their functional evaluation is under way (Tomohiro Yamaki, Mirca Saurty).

On the basis of the results we obtained, we design novel molecular tools to question further the dynamics of tumor cell functional heterogeneity, and its impact on malignant glioma growth (Ghislaine Morvan-Dubois). 

Résultats importants

The results we obtained in the past two years provided totally novel and unexpected insights into the manner according to which interactions between extracellular cues and intrinsic cancer cell properties ultimately integrate into specific and coordinated changes in the molecular mechanisms governing acquisition/maintenance of the stem and tumor-initiating properties of GSC. The interdependence of metabolism and epigenetic regulation and the dependence of both on enzymatic activities render them highly attractive for therapeutic targeting. 

However, the consequences of metabolic reprogramming on epigenetic regulation in cancer cells, and subsequent tumor behavior, are still poorly understood. We will keep exploring in details the links between metabolism reprogramming and stem properties of cancer cells. In addition, we will pursue our characterization of the epigenetic regulations altered in GSC having exited the stem state. This comprehensive characterization of the molecular substrates of GSC behavior will be completed with the search for the molecular cues governing the dialog between GSC and their environment, thought to be crucial for preserving the cells in a stem-like state.

Collaborations

  • F. Boussin, Fontenay, France ; DNA repair mechanisms
  • J. Gavard, Nantes, France ; cerebral endothelial cells and angiogenesis
  • M. Goodhart, Paris, France ; chromatin modifyers
  • J. Haiech, M.C. Killhofer, Strasbourg ; pharmacology
  • P Korkolopoulou, Athens, Greece; neuropathology of cerebral tumors
  • A Miller, Hong-Kong, China; calcium sensors
  • J Meier, Berlin, Germany; receptor channels
  • M. Moreau, Toulouse, France; calcium signaling
  • V. Moura-Neto, Rio de Janeiro, Brazil; neuroanatomy and brain tumors
  • S. Ohta, Tokyo, Japan
  • C Ottolenghi, Paris, France; metabolism
  • P Varlet, Paris; neuropathology of cerebral tumors
  • T. Virolle, Nice ; micro-RNAs