Oncotarget

Research Papers:

New in vivo avatars of diffuse intrinsic pontine gliomas (DIPG) from stereotactic biopsies performed at diagnosis

Alexandre Plessier, Ludivine LeDret, Pascale Varlet, Kevin Beccaria, Joelle Lacombe, Sebastien Meriaux, Francoise Geffroy, Laurence Fiette, Patricia Flamant, Fabrice Chretien, Thomas Blauwblomme, Stephanie Puget, Jacques Grill, Marie-Anne Debily and David Castel _

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Oncotarget. 2017; 8:52543-52559. https://doi.org/10.18632/oncotarget.15002

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Abstract

Alexandre Plessier1,*, Ludivine Le Dret1,*, Pascale Varlet2, Kévin Beccaria3, Joëlle Lacombe2, Sébastien Mériaux4, Françoise Geffroy4, Laurence Fiette5, Patricia Flamant5, Fabrice Chrétien2,5, Thomas Blauwblomme3, Stéphanie Puget3, Jacques Grill1,6, Marie-Anne Debily1,7,** and David Castel1,6,**

1UMR8203 “Vectorologie & Thérapeutiques Anticancéreuses”, CNRS, Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, Villejuif, France

2Department of Neuropathology, Hôpital Sainte-Anne, Université Paris V Descartes, Sorbonne Paris Cité, Paris, France

3Department of Pediatric Neurosurgery, Hôpital Necker-Enfants Malades, Université Paris V Descartes, Sorbonne Paris Cité, Paris, France

4UNIRS, Neurospin, I2BM, Direction de la Recherche Fondamentale, Commissariat à l’Energie Atomique et aux Energies Alternatives, Gif-sur-Yvette, France

5Institut Pasteur, Histopathology and Animal Models, Université Paris V Descartes, Sorbonne Paris Cité, Paris, France

6Département de Cancérologie de l’Enfant et de l’Adolescent, Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, Villejuif, France

7Université d’Evry-Val d’Essonne, Evry, France

*These two co-authors contributed equally to the work

**Co-senior authors

Correspondence to:

David Castel, email: david.castel@gustaveroussy.fr

Marie-Anne Debily, email: marie-anne.debily@gustaveroussy.fr

Keywords: brain tumor model, child, tumor-initiating cell, infiltrative midline glioma with histone H3-K27M mutation, bioluminescence

Received: August 04, 2016    Accepted: January 10, 2017    Published: February 02, 2017

ABSTRACT

Diffuse Instrinsic Pontine Glioma is the most aggressive form of High Grade Gliomas in children. The lack of biological material and the absence of relevant models have hampered the development of new therapeutics. Their extensive infiltration of the brainstem renders any surgical resection impossible and until recently biopsies were considered not informative enough and therefore not recommended. Thus, most models were derived from autopsy material. We aimed to develop relevant in vivo DIPG models that mimic this specific disease and its molecular diversity from tumor material obtained at diagnosis. Eight patient-derived orthotopic xenograft models were obtained after direct stereotactic injection of a mixed cell suspension containing tumor cells and stromal cells in the brainstem or thalamus of nude mice and serially passaged thereafter. In parallel, we developed 6 cell-derived xenograft models after orthotopic injection of tumor-initiating cells cultured from stereotactic biopsies. Cells were modified to express luciferase to enable longitudinal tumor growth monitoring, and fluorescent reporter proteins to trace the tumor cells in the brain.

These models do not form a tumor mass, they are invasive, show the H3K27 trimethylation loss in vivo and the tumor type diversity observed in patients in terms of histone H3 mutations and lineage markers. Histological and MRI features at 11.7 Tesla show similarities with treatment naïve human DIPG, and in this respect, both direct and indirect orthotopic xenograft looked alike. These DIPG models will therefore constitute valuable tools for evaluating new therapeutic approaches in this devastating disease.


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