Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity
- Brain Tumor
- Cancer stem cells
- Intra-tumor heterogeneity
- Epigenetic regulation
Glioblastomas (GBM) are the most common form of primary brain tumors in adult. These tumors remain incurable and lead to a fatal outcome in less than 18 months. Tumor development is a complex process mixing normal cells and heterogeneous cancer cell populations. A sublevel of complexity in intra-tumor heterogeneity resides in the co-existence of functionally divergent heterogeneous populations of cells. GBM exemplifies this situation by harboring tumor territories functionally divergent while sharing similar genomic abnormalities. These territories are enriched in mitotic tumor cells, positive for markers of GBM stem cell (GSC), or enriched in non-mitotic, differentiated cells, frequently associated to pathological vessels and large necrotic areas. Such heterogeneity constitutes a major obstacle for conventional therapies, mostly due to the selection and expansion of resistant GSC. Thus targeting GSC properties and mitotic territories will be valuable for therapeutic strategies.
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 platform dedicated to establish and characterize a collection of GSC primary cultures (from different patients) as well as GBM samples representative of mitotic and non-mitotic tumor territories. This collection, crucial for our research, allowed us to identify key molecular factors involved in the control of GSC properties and tumorigenicity.
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.
We have identified a tumor suppressor miRNA signature (among them the miR-302-367 cluster), constituting a feature and a gatekeeper of non-mitotic territories, while one of its common targets, a splice factor, is restricted to stem-like/progenitor cells in mitotic territories and contributes to the maintenance of stemness and selfrenewal.
We will characterize the regulation of this splice factor and its mode of action in self-renewing GSC by identifying its most functionally prominent targets (deep RNAseq, exome analysis and CLIP-seq). Our recent results indicate the strong contribution of this factor in the regulation of H3K9 and H3K27 methylation, influencing thus the chromatin structure. Using bioinformatic and mathematical modeling, we will determine hubs of regulatory targets involved in GSC maintenance and aggressiveness.
Signals coming from the tumor microenvironment including soluble proteins, extracellular matrix components, secreted vesicles as well as tunneling nanotubes (TNT) are most likely important factors to guide GBM cell fate decision. This part of our project is to functionally characterize these cell-to-cell communication processes and verify their contribution in the genesis of functionally divergent tumor territories.
The development of molecules capable in promoting irreversible loss of CSC populations, through the modulation of the specific factors that we identified (miRNA, transcription factors, splice factors), will constitute an innovative and attractive therapeutic approach compatible with industrial pipelines. We develop in tight collaborations with chemists (Dr M Duca, ICN Nice; Dr F Roussy, Dr M Litaudon, ICSN Gyf sur Yvette) the characterization of innovative compounds targeting GSC.
- Almairac, F, Turchi, L, Sakakini, N, Debruyne, DN, Elkeurti, S, Gjernes, E et al.. ERK-mediated loss of miR-199a-3p and induction of EGR1 act as a "toggle switch" of GBM cell dedifferentiation into NANOG- and OCT4-positive cells. Cancer Res. 2020; :. doi: 10.1158/0008-5472.CAN-19-0855. PubMed PMID:32366479 .
- Torres, Á, Erices, JI, Sanchez, F, Ehrenfeld, P, Turchi, L, Virolle, T et al.. Extracellular adenosine promotes cell migration/invasion of Glioblastoma Stem-like Cells through A3 Adenosine Receptor activation under hypoxia. Cancer Lett. 2019;446 :112-122. doi: 10.1016/j.canlet.2019.01.004. PubMed PMID:30660649 .
- Virolle, T. [Cancer stem cells in glioblastoma]. Bull Cancer. 2017;104 (12):1075-1079. doi: 10.1016/j.bulcan.2017.10.012. PubMed PMID:29153545 .
- Bogeas, A, Morvan-Dubois, G, El-Habr, EA, Lejeune, FX, Defrance, M, Narayanan, A et al.. Changes in chromatin state reveal ARNT2 at a node of a tumorigenic transcription factor signature driving glioblastoma cell aggressiveness. Acta Neuropathol. 2018;135 (2):267-283. doi: 10.1007/s00401-017-1783-x. PubMed PMID:29149419 PubMed Central PMC5773658.
- Dadone-Montaudié, B, Ambrosetti, D, Dufour, M, Darcourt, J, Almairac, F, Coyne, J et al.. [18F] FDOPA standardized uptake values of brain tumors are not exclusively dependent on LAT1 expression. PLoS ONE. 2017;12 (9):e0184625. doi: 10.1371/journal.pone.0184625. PubMed PMID:28937983 PubMed Central PMC5609741.
- Debruyne, DN, Turchi, L, Burel-Vandenbos, F, Fareh, M, Almairac, F, Virolle, V et al.. DOCK4 promotes loss of proliferation in glioblastoma progenitor cells through nuclear beta-catenin accumulation and subsequent miR-302-367 cluster expression. Oncogene. 2018;37 (2):241-254. doi: 10.1038/onc.2017.323. PubMed PMID:28925399 .
- Fareh, M, Almairac, F, Turchi, L, Burel-Vandenbos, F, Paquis, P, Fontaine, D et al.. Cell-based therapy using miR-302-367 expressing cells represses glioblastoma growth. Cell Death Dis. 2017;8 (3):e2713. doi: 10.1038/cddis.2017.117. PubMed PMID:28358371 PubMed Central PMC5386523.
- El-Habr, EA, Dubois, LG, Burel-Vandenbos, F, Bogeas, A, Lipecka, J, Turchi, L et al.. A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma. Acta Neuropathol. 2017;133 (4):645-660. doi: 10.1007/s00401-016-1659-5. PubMed PMID:28032215 PubMed Central PMC5348560.
- Papin-Michault, C, Bonnetaud, C, Dufour, M, Almairac, F, Coutts, M, Patouraux, S et al.. Study of LAT1 Expression in Brain Metastases: Towards a Better Understanding of the Results of Positron Emission Tomography Using Amino Acid Tracers. PLoS ONE. 2016;11 (6):e0157139. doi: 10.1371/journal.pone.0157139. PubMed PMID:27276226 PubMed Central PMC4898730.
- Sakakini, N, Turchi, L, Bergon, A, Holota, H, Rekima, S, Lopez, F et al.. A Positive Feed-forward Loop Associating EGR1 and PDGFA Promotes Proliferation and Self-renewal in Glioblastoma Stem Cells. J. Biol. Chem. 2016;291 (20):10684-99. doi: 10.1074/jbc.M116.720698. PubMed PMID:27002148 PubMed Central PMC4865916.
- Burel-Vandenbos, F, Ngo-Mai, M, Dadone, B, Di Mauro, I, Gimet, S, Saada-Bouzid, E et al.. MET immunolabelling is a useful predictive tool for MET gene amplification in glioblastoma. Neuropathol. Appl. Neurobiol. 2017;43 (3):252-266. doi: 10.1111/nan.12320. PubMed PMID:26946354 .
- Burel-Vandenbos, F, Turchi, L, Benchetrit, M, Fontas, E, Pedeutour, Z, Rigau, V et al.. Cells with intense EGFR staining and a high nuclear to cytoplasmic ratio are specific for infiltrative glioma: a useful marker in neuropathological practice. Neuro-oncology. 2013;15 (10):1278-88. doi: 10.1093/neuonc/not094. PubMed PMID:23935154 PubMed Central PMC3779042.
- Serres, E, Debarbieux, F, Stanchi, F, Maggiorella, L, Grall, D, Turchi, L et al.. Fibronectin expression in glioblastomas promotes cell cohesion, collective invasion of basement membrane in vitro and orthotopic tumor growth in mice. Oncogene. 2014;33 (26):3451-62. doi: 10.1038/onc.2013.305. PubMed PMID:23912459 .
- Nayernia, Z, Turchi, L, Cosset, E, Peterson, H, Dutoit, V, Dietrich, PY et al.. The relationship between brain tumor cell invasion of engineered neural tissues and in vivo features of glioblastoma. Biomaterials. 2013;34 (33):8279-90. doi: 10.1016/j.biomaterials.2013.07.006. PubMed PMID:23899445 .
- Turchi, L, Debruyne, DN, Almairac, F, Virolle, V, Fareh, M, Neirijnck, Y et al.. Tumorigenic potential of miR-18A* in glioma initiating cells requires NOTCH-1 signaling. Stem Cells. 2013;31 (7):1252-65. doi: 10.1002/stem.1373. PubMed PMID:23533157 .
- Fareh, M, Turchi, L, Virolle, V, Debruyne, D, Almairac, F, de-la-Forest Divonne, S et al.. 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. Cell Death Differ. 2012;19 (2):232-44. doi: 10.1038/cdd.2011.89. PubMed PMID:21720384 PubMed Central PMC3263498.
- Burel-Vandenbos, F, Benchetrit, M, Miquel, C, Fontaine, D, Auvergne, R, Lebrun-Frenay, C et al.. EGFR immunolabeling pattern may discriminate low-grade gliomas from gliosis. J. Neurooncol. 2011;102 (2):171-8. doi: 10.1007/s11060-010-0308-4. PubMed PMID:20652725 .
- Rostagno, P, Wolchinsky, Z, Vigano, AM, Shivtiel, S, Zhou, H, Van Bokhoven, H et al.. Embryonic stem cells as an ectodermal cellular model of human p63-related dysplasia syndromes. Biochem. Biophys. Res. Commun. 2010;395 (1):131-5. doi: 10.1016/j.bbrc.2010.03.154. PubMed PMID:20361935 .
- Turchi, L, Fareh, M, Aberdam, E, Kitajima, S, Simpson, F, Wicking, C et al.. ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress. Cell Death Differ. 2009;16 (5):728-37. doi: 10.1038/cdd.2009.2. PubMed PMID:19219066 .
- Preynat-Seauve, O, Suter, DM, Tirefort, D, Turchi, L, Virolle, T, Chneiweiss, H et al.. Development of human nervous tissue upon differentiation of embryonic stem cells in three-dimensional culture. Stem Cells. 2009;27 (3):509-20. doi: 10.1634/stemcells.2008-0600. PubMed PMID:19074418 .
2014 - Prix de l'appel à projet santé du conseil général 06 - Conseil départemental
1998 - prix Coloplast - entreprise Coloplast
iBV - Institut de Biologie Valrose
Université Nice Sophia Antipolis
Faculté des Sciences
06108 Nice cedex 2