Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity

Glioblastomas (GBM) are the most common form of primary brain tumors afflicting adult patients of all ages. These vascularized and infiltrating tumors remain incurable and lead to a fatal outcome in less than 18 months. The research developed by our group focuses on the study of the regulation of GSC plasticity in the context of the genesis of tumor micro-territories. Through a better understanding of tumor homeostasis, our goal is to identify key molecular factors of interest for therapeutic purposes. The group is composed of researchers and clinicians, an essential association to link fundamental research with clinical applications. Because GBM are heterogeneous tumors, we have built a multicentric platform dedicated to establish and characterize a collection of GSC primary cultures (from different patients. This collection, crucial for our researchs, allowed us to identify key molecular factors involved in the control of GSC properties and tumorigenicity.

Tumor development is a complex process mixing normal cells and heterogeneous cancer cell populations. Besides genomic abnormalities, a sublevel of complexity in intra-tumor heterogeneity resides in the co-existence of populations of cells (stem-like, progenitors or differentiated tumor cells) functionally divergent and represented in variable proportions within tumors. Glioblastoma (GBM), the most common form of primary brain tumors, exemplifies this situation and harbors within the dense tumor, tumor territories functionally divergent while sharing similar genomic abnormalities. These territories are either enriched in mitotic tumor cells most often positive for markers of GBM stem-like cell (GSC), or enriched in non-mitotic, indolent cells, frequently associated to pathological vessels and large necrotic areas. Such a functional heterogeneity confuses the prognosis and constitutes a major obstacle for conventional anti-tumor therapies, mostly due to the resistance of the stem/progenitor cell population. In this context, we have identified a miR signature (among them the miR-302-367 cluster), constituting a feature and a gatekeeper of non-mitotic territories, while one of its targets, the splice factor SFX, is restricted to stem-like/progenitor cells in mitotic territories and contributes to the maintenance of their stemness and selfrenewal.

The objective of our research development is to model the molecular basis involved in the biogenesis and homeostasis of both mitotic and non-mitotic tumor territories, affecting tumor progression and aggressiveness. Our aim is to identify innovative therapeutic targets capable to efficiently repress GSC properties.

To achieve this goal we shall pursue the following objectives:

A) Characterization of SFX role in stemness maintenance, regulation and mode of action.

We will determine the consequence of SFX repression on GSC stemness, resistance to treatement and tumorigenicity. In addition we will characterize the regulation of SFX in self-renewing GSC as well as its mode of action by identifying its most functionally prominent targets (deep RNAseq, exome analysis and CLIP-seq). Interestingly, our recent results indicate the strong contribution of SFX in the regulation of histone marks. Bioinformatic and mathematical modeling (collaboration C. Pasquier, I3S CNRS) of our results will determine hubs of regulatory network involved in stemness promotion and therefore in the genesis of functionally divergent tumor micro-territories.

B) Identification of environmental signals and pathways involved in the segregation of mitotic/undifferentiated and non-mitotic/differentiated tumor territories (Collaboration with P Thérond, iBV, Nice; M L Vignais, A Parmegianni, B Charlot, Univ. Montpellier, CNRS)

Signals coming from the tumor microenvironments including soluble proteins, extracellular matrix components and secreted vesicles by tumor or normal cells are most likely important factors to guide the cell fate decision. This part of the project aims to identify and characterize, from our collection of collection of GBM samples representative of mitotic/undifferentiated and non-mitotic/differentiated tumor territories (n=20), effectors involved in triggering stemness or a more differentiated non-mitotic state. In addition we have observed that nanovesicles secreted from differentiated or undifferentiated GBM cells, as well as the formation of tubes, could be critical factors for cell fate decision. This part of our project is to functionally characterize this cell to cell communication processes and verify their contribution in the genesis of functionally divergent tumor territories.

C) Design and characterization of small molecules capable to interfere with miRNA expression : turning GSC into indolent cells.

The development of molecules capable to promote irreversible loss of the tumorigenic CSC population through modulation of specific miRNA signatures will constitute an innovative and attractive therapeutic approach for clinicians, and compatible with industrial pipelines. A proof of principle of this approach developed in tight collaboration with Dr M Duca (Institut de Chimie de Nice ICN, Nice), is given by our discovery of the DVXXX compound, which induce to GSC, loss of stemness and clonal proliferation while sensitizing them to conventional chemotherapy. These effects are reminiscent to miR-302-367 effects when overexpressed in GSC. In vivo proof on principle of this compound as well as pre-clinical studies are ongoing (premat and mat SATT sud est). Other molecules susceptible to be used for GBM treatment and developed by Drs F Roussy and M Litaudon are also tested in the laboratory.

Collaborations :

Hervé CHNEIWEISS, Marie Pierre Junier, Inserm U1130, CNRS UMR 8246, Université P. & M. Curie

Jean Philippe Hugnot, INM Montpellier

Marie Luce Vignais, univ Montpellier

Corinne Auge-Guillou, univ Tours

Jean IMBERT, INSERM U928, plateforme IBISA, Marseille

Dominique FIGARELLA-BRANGER, Hopital de la Timone, CRO2 Marseille

Olivier Preynat-Sauves, université de médecine, Genève

Maria Duca, ICN Nice

Fanny Roussy, Marc Litaudon, ICSN Gyf sur Yvette

 

Last publications

A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma. - 2016 - Acta neuropathologica - El-Habr EA, Dubois LG, Burel-Vandenbos F, Bogeas A, Lipecka J, Turchi L, Lejeune FX, Coehlo PL, Yamaki T, Wittmann BM, Fareh M, Mahfoudhi E, Janin M, Narayanan A, Morvan-Dubois G, Schmitt C, Verreault M, Oliver L, Sharif A, Pallud J, Devaux B, Puget S, Korkolopoulou P, Varlet P, Ottolenghi C, Plo I, Moura-Neto V, Virolle T, Chneiweiss H, and Junier,MP

A Positive Feed-forward Loop Associating EGR1 and PDGFA Promotes Proliferation and Self-renewal in Glioblastoma Stem Cells. - 2016 - The Journal of biological chemistry - 291 P10684-99 - Sakakini N, Turchi L, Bergon A, Holota H, Rekima S, Lopez F, Paquis P, Almairac F, Fontaine D, Baeza-Kallee N, Van Obberghen-Schilling E, Junier MP, Chneiweiss H, Figarella-Branger D, Burel-Vandenbos F, Imbert J, and Virolle,T

MET immunolabeling is a useful predictive tool for MET gene amplification in glioblastoma. - 2016 - Neuropathology and applied neurobiology - Burel-Vandenbos F, Ngo-Mai M, Dadone B, Di Mauro I, Gimet S, Saada-Bouzid E, Bourg V, Almairac F, Fontaine D, Virolle T, and Pedeutour,F

Fibronectin expression in glioblastomas promotes cell cohesion, collective invasion of basement membrane in vitro and orthotopic tumor growth in mice. - 2014 - Oncogene - 33 P3451-62 - Serres E, Debarbieux F, Stanchi F, Maggiorella L, Grall D, Turchi L, Burel-Vandenbos F, Figarella-Branger D, Virolle T, Rougon G, and Van Obberghen-Schilling,E

Cells with intense EGFR staining and a high nuclear to cytoplasmic ratio are specific for infiltrative glioma: a useful marker in neuropathological practice. - 2013 - Neuro-oncology - 15 P1278-88 - Burel-Vandenbos F, Turchi L, Benchetrit M, Fontas E, Pedeutour Z, Rigau V, Almairac F, Ambrosetti D, Michiels JF, and Virolle,T

The relationship between brain tumor cell invasion of engineered neural tissues and in vivo features of glioblastoma. - 2013 - Biomaterials - 34 P8279-90 - Nayernia Z, Turchi L, Cosset E, Peterson H, Dutoit V, Dietrich PY, Tirefort D, Chneiweiss H, Lobrinus JA, Krause KH, Virolle T, and Preynat-Seauve,O

Tumorigenic potential of miR-18A* in glioma initiating cells requires NOTCH-1 signaling. - 2013 - Stem cells (Dayton, Ohio) - 31 P1252-65 - Turchi L, Debruyne DN, Almairac F, Virolle V, Fareh M, Neirijnck Y, Burel-Vandenbos F, Paquis P, Junier MP, Van Obberghen-Schilling E, Chneiweiss H, and Virolle,T

The miR 302-367 cluster drastically affects self-renewal and infiltration properties of glioma-initiating cells through CXCR4 repression and consequent disruption of the SHH-GLI-NANOG network. - 2012 - Cell death and differentiation - 19 P232-44 - Fareh M, Turchi L, Virolle V, Debruyne D, Almairac F, de-la-Forest Divonne S, Paquis P, Preynat-Seauve O, Krause KH, Chneiweiss H, and Virolle,T

EGFR immunolabeling pattern may discriminate low-grade gliomas from gliosis. - 2011 - Journal of neuro-oncology - 102 P171-8 - Burel-Vandenbos F, Benchetrit M, Miquel C, Fontaine D, Auvergne R, Lebrun-Frenay C, Cardot-Leccia N, Michiels JF, Paquis-Flucklinger V, and Virolle,T

Embryonic stem cells as an ectodermal cellular model of human p63-related dysplasia syndromes. - 2010 - Biochemical and biophysical research communications - 395 P131-5 - Rostagno P, Wolchinsky Z, Vigano AM, Shivtiel S, Zhou H, Van Bokhoven H, Ferone G, Missero C, Mantovani R, Aberdam D, and Virolle,T

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