Research Projects
Our team has been studying the deregulation of apoptosis in tumours of the central nervous system for many years. Our goal, besides a better understanding of basic mechanisms of apoptosis, is to provide new platforms for the design of clinical tests and/or new tools to enhance the activity of current treatments of Glioblastoma multiform (GBM), the most common brain tumor in adults. These tumors have been shown to be particularly refractory to apoptosis and other cell death mechansims. Since cancer stem cells played a crucial role in tumor resistance to treatment and recurrence, we generatd a series of 3D primary cultures derived from human GBM, grown in various conditions to favor stem cell maintenance or to promote cell differentiatin. This unique collection has been used in most of our study to investigate several research axes :
1/ Autocrine and paracrine regulation of apoptosis
We have shown that the induction of apoptosis coincides with an increase in the synthesis of PGE2, which plays an active role in Bax activation. Numerous reports have emphasized the anti-apoptotic roles of PGE2 and its negative role during tumor progression. However, after irradiation, we have shown that in our model PGE2 promoted tumor survival and repopulation through the activation of the EGFR, especially in the context of growth factors deprivation.
2/Genomic and epigenetic analyses of glioblastoma
We have analyzed the impact of aberrant DNA methylation profile for genes encoding proteins implicated in apoptotic processes and show a possible cause of cancer cell resistance. Interestingly, we have demonstrated that folate, a DNA methylating agent, is a possible adjuvant in anti-glioma therapeutic protocols. From these results , a clinical study has been initiated to evaluate anti-glioma property of folate in combination with standard treatment.
3/ Tumor metabolism and apoptosis
Metabolism is essential in the regulation and outcome of glioma progression, in particular through the Warburg effect. A proteomic analysis between neural stem cells and cancer stem cells revealed that PKM2, an glycolytic enzyme, inhibits cell death through the control of differentiation only in cancer stem cells. Similarly, we found that mesenchymal stem cells, like cancer stem cells, are highly resistant to apoptosis and exhibit high autophagic activity until early differentiation. Finally, fine tumor metabolic studies highlighted bioenergetic differences depending on the moecular subtype of GBM.
Staff
F. M. Vallette, DR INSERM
D. Heymann, PU-PH ICO
E. Bonnelye, CR CNRS
P.F. Cartron, CR INSERM
L. Lalier, CR ICO
C. Olivier, MCU
A. Serandour, MC-ECN/Chaire INSERM
A. Renodon-Cornière, CR CNRS
M.F Heymann, MCU-PH ICO
S. Supiot, PH ICO
J. Raimbourg, PH ICO
C. Salaud, Doctorant
J. Briand, Doctorant
M. Cadé, Doctorant
M. Duforestel, Doctorant
O. Bosson, Doctorant
A. Loussouarn, Doctorant
L. Oliver, IR CHU
V. Potiron, IR ICO
D. Cochonneau, IR ICO
N. Dubois, IR ICO
G. Cartron, Chef de projet, ICO
M. Pietri, IE ICO
A. Nadaradjane, TN Univ
D. Lanöe, TN ICO
M.P Joalland, TN ICO
E. Moranton, TN ICO
Main publications
1. C Gratas, Q Séry, M Rabé, L Oliver, FM Vallette. Bak and Mcl-1 are essential for Temozolomide induced cell death in human glioma. Oncotarget. (2014)
2. PF Cartron, E Hervouet, E Debien, C Olivier, D Pouliquen, J Menanteau, D Loussouarn, SA Martin, M Campone, FM Vallette. Folate supplementation limits the tumourigenesis in rodent models of gliomagenesis. Eur J Cancer. (2012)
3. M Cheray, R Pacaud, A Nadaradjane, L Oliver, FM Vallette, PF Cartron. Specific Inhibition of DNMT3A/ISGF3γ Interaction Increases the Temozolomide Efficiency to Reduce Tumor Growth. Theranostics. (2016)
http://www.hal.inserm.fr/inserm-01414173
4. M Morfouace, L Lalier, L Oliver, M Cheray, C Pecqueur, PF Cartron, FM Vallette. Control of glioma stem cell death and differentiation by a PKM2-Oct4 complex. Cell Death Dis. (2014)
5. K Oizel, C Gratas, A Nadaradjane, L Oliver, FM Vallette, C Pecqueur. D-2-Hydroxyglutarate does not mimic all the IDH mutation effects, in particular the reduced etoposide-triggered apoptosis mediated by an alteration in mitochondrial NADH. Cell Death Dis. (2015)
Thesis Defense
K. Oizel, Doctorant (10/2015)
M. Pacaud, Doctorant (12/2015)
Imprimer
