| Team 4: Jean-François Peyron | |||
| INFLAMMATION, CANCER AND CANCER STEM CELLS | |||
| Previous activities | |||
The projects that are being developped by team#4 "Inflammation, Cancer, Cancer Stem Cells" aim at a better understanding of the pathological mechanisms that sustain human acute leukemia ; in order to identify new molecular targets or active molecules for innovative therapeutical strategies. The research is conducted at fundamental and pre-clinical levels, backed by the use of relevant murine cancer models and by an active relationship with the Oncopediatric department at the hospital next door (Hôpital de l'Archet, CHU-Nice). 3 main axis are open : 1- studying the leukemic-reprogrammed metabolism to identify deregulated genes involved in metabolic addictions that can be used as new targets. 2- analyzing the pathologic properties of leukemic stem cells/leukemia initiating cells both at the roots of the disease and also responsible for relapse and treatment failure. 3- investigating the role of the NF-kappaB transcription factor as a support for abnormal survival, proliferation and resistance to treatments. The first research axis is based a murine model that is representative of human T-cell Acute Lymphoblastoid Leukemia (T-ALL) or T-cell Lymphoblastoid Lymphoma (T-LL). It is generated by the deletion of the PTEN tumor suppressor, specifically in T cells (cre-lox technology, tPTEN-/- mice). Using tPTEN-/- mice, the team is studying the biochemical and genetic deregulations associated with T-cell transformation to find hits for future targeted therapies. During transformation, cancer cells reprogram their metabolism to face the energetic challenges associated with intense abnormal cell division. Through this process, the cells develop metabolic addictions that could represent their Achille's heels if targeted by specific drugs. Physiologically, PTEN is the unique biochemical brake to activation of the PI3K/Akt/mTORC pathway that transmits growth and proliferation signals and which is found abnormaly active at a high frequency in human leukemia. In particular, the mTORC1 branch is crucial to support growth through stimulation of lipid, nucleic acid and protein synthesis. Recently, the team has shown that the anti-diabetic drug metformin induced leukemic cell death after downregulating mTORC1 (Rosilio, 2012, 2013. Cancer Letters). Besides, we also uncovered a strong addiction to Essential Amino Acid (EAA) visualized by the overexpression of the EAA transporter LAT1 and demonstrated that targeting LAT1 triggered a cell death response (Rosilio 2015. Leukemia). Using various bioinformatic analyses (GSEA, CMAP) of the tPTEN-/- gene expression profile (GSE39591), we are mining the transcriptomic data to identify the genes that drive leukemia and in particular those which are associated with metabolic reprogrammation. Candidate genes are then biologically evaluated through various in vitro and in vivo approaches including small animal imaging. The second research axis concerns the study of Leukemia initiating cells (LICs). A first investigation is based on the use of a proprietary ex vivo niche-like culture system (NLCS : Griessinger, 2014. Stem Cells Transl Med) that allows the mantainance of LICs and chemo-resistant LICs from Acute Myeloid Leukemia (AML), as well as the quantification of their dynamic properties. The NLCS is used to dissect the pathological properties of LICs, to ameliorate AML patient prognosis and as a screening platform to identify LIC-targeting molecules. In a second approach, we are studying the role of the BMI1 polycomb protein that is crucial for normal and leukemic stem cells. Through RNA interference, we have identified and are characterizing a new effector of BMI1 that is involved in regulation of autophagy to maintain the stemness state and to support acute transformation of Chronic Myeloid Leukemic cells (Mourgues, 2015. Leukemia). In a third research axis we are dissecting the role of the NF-kappaB transcription factor in the tPTEN-/- mouse model. For this, we have generated double KO mice to either inactivate (DKO : PTEN-/-IKK2-/- and PTEN-/-RelA-/-) or constitutively activate (DKO : PTEN-/-IkBa-/-) the NF-kB pathway in vivo. We are now searching for NF-kB target genes that are involved in transformation, LIC maintainance and metabolism reprogramming. Key words : Leukemia, Leukemia-initiating cells, self-renewal, metabolism, resistance, Cre-lox mice, PTEN, NF-kB, Bmi-1 ; signaling, transcriptomics, bioinformatics. |
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| Major Publications | |||
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2015 Mourgues L, Imbert V, Nebout M, Colosetti P, Neffati Z, Lagadec P, Verhoeyen E, Peng C, Duprez E, Legros L, Rochet N, Maguer-Satta V, Nicolini FE, Mary D, Peyron JF. The BMI1 polycomb protein represses CyclinG2-induced autophagy to support proliferation in Chronic Myeloid Leukemia cells. Leukemia. 2015 Apr 30 2014 Rosilio C, Nebout M, Imbert V, Griessinger E, Neffati Z, Benadiba J, Hagenbeek T, Spits H, Reverso J, Ambrosetti D, Michiels JF, Bailly-Maitre B, Endou H, Wempe MF, Peyron JF. L-type amino-acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia. Leukemia. 2014 Dec 8. Pontier-Bres R, Munro P, Boyer L, Anty R, Imbert V, Terciolo C, André F, Rampal P, Lemichez E, Peyron JF, Czerucka D. Saccharomyces boulardii Modifies Salmonella Typhimurium Traffic and Host Immune Responses along the Intestinal Tract. PLoS One. 2014 Aug 13;9(8) Rosilio C, Ben-Sahra I, Bost F, Peyron JF. Metformin: A metabolic disruptor and anti-diabetic drug to target human leukemia. Cancer Lett. 2014 Jan 22. 2013 Rosilio C, Lounnas N, Nebout M, Imbert V, Hagenbeek T, Spits H, Asnafi V, Pontier-Bres R, Reverso J, Michiels JF, Sahra IB, Bost F, Peyron JF. The metabolic perturbators metformin, phenformin and AICAR interfere with the growth and survival of murine PTEN-deficient T cell lymphomas and human T-ALL/T-LL cancer cells. Cancer Lett. 2013 Aug 9;336(1):114-26. Lounnas N, Rosilio C, Nebout M, Mary D, Griessinger E, Neffati Z, Chiche J, Spits H, Hagenbeek TJ, Asnafi V, Poulsen SA, Supuran CT, Peyron JF, Imbert V. Pharmacological inhibition of carbonic anhydrase XII interferes with cell proliferation and induces cell apoptosis in T-cell lymphomas. Cancer Lett. 2013 Jun 1;333(1):76-88. Chami L, Buggia-Prévot V, Duplan E, Delprete D, Chami M, Peyron JF, Checler F. Nuclear factor-κB regulates βAPP and β- and γ-secretases differently at physiological and supraphysiological Aβ concentrations. J Biol Chem. 2013 Jul 5;288(27):19645. 2012 Pontier-Bres R, Prodon F, Munro P, Rampal P, Lemichez E, Peyron JF, Czerucka D. Modification of Salmonella Typhimurium motility by the probiotic yeast strain Saccharomyces boulardii. PLoS One. 2012;7(3) 2011 Fenouille N, Grosso S, Su Y, Mary D, Pontier-Bres R, Imbert V, Czerucka D, Caroli-Bosc FX, Peyron JF, Lagadec P. Calpain 2-dependent IκB-α degradation mediates cpt-11 secondary resistance in colorectal cancer xenografts. J Pathol. 2011 Nov 8. Martins FS, Dalmasso G, Arantes RM, Doye A, Lemichez E, Lagadec P, Imbert V, Peyron JF, Rampal P, Nicoli JR, Czerucka D. Interaction of Saccharomyces boulardii with Salmonella enterica serovar Typhimurium protects mice and modifies T84 cell response to the infection. PLoS One. 2010 Jan 27;5(1):e8925. 2010 Martins FS, Dalmasso G, Arantes RM, Doye A, Lemichez E, Lagadec P, Imbert V, Peyron JF, Rampal P, Nicoli JR, Czerucka D. Interaction of Saccharomyces boulardii with Salmonella enterica serovar Typhimurium protects mice and modifies T84 cell response to the infection. PLoS One. 2010 Jan 27;5(1):e8925. 2009 Lounnas, N., Frelin, C., Gonthier, N., Colosetti, P., Sirvent, A., Cassuto, J.P., Berthier, F., Sirvent, N., Rousselot, P., Dreano, M., et al. (2009). NF-kappaB inhibition triggers death of imatinib-sensitive and imatinib-resistant chronic myeloid leukemia cells including T315I Bcr-Abl mutants. International journal of cancer 125 : 308-317. 2008 Griessinger E, Frelin C, Cuburu N, Imbert V, Dageville C, Hummelsberger M, Sirvent N, Dreano M and Peyron JF. Preclinical targeting of NF-kappaB and FLT3 pathways in AML cells. Leukemia, 2008, 22(7): 1466-1469.
Frelin C, Imbert V, Griessinger M, Peyron AC, Rochet N, Philip P, Dageville C, Sirvent A, Hummelsberger M, Berard E, Dreano M, Sirvent N, Peyron J-F. Targeting NF-kB via pharmacological inhibition of IKK2 induced apoptosis of human Acute Myeloid Leukemia cells. 2005. Blood. 105. 805-811. Frelin C, Imbert V, Griessinger E, Loubat A, Dreano M, Peyron J-F. AS602868, a pharmacological inhibitor of IKK2, reveals the apoptotic potential of TNF-alpha in Jurkat leukemic cells. 2003. Oncogene. 22. 8187-8194. Piche T, des Varannes SB, Sacher-Huvelin S, Holst JJ, Cuber JC, Galmiche JP. Colonic fermentation influences lower esophageal sphincter function in gastroesophageal reflux disease. 2003. Gastroenterology.124. 894-902. Dahan S, Busuttil V, Imbert V, Peyron J-F, Rampal P, Czerucka D. Enterohemorrhagic Escherichia coli infection induces Interleukin-8 production via activation of Mitogen-activated Protein kinases and the transcription factors NF-kappa B and AP-1 in T84 cells.2002. Infection and Immunity. 70. 2304-2310. Bottero V, Busuttil V, Loubat A, Magné N, Fischel JL, Milano G, Peyron J-F. Activation of NF-kB through the IKK complex by the topoisomerase poisons SN38 and doxorubicin : a brake to apoptosis in HeLa human carcinoma cells. 2001. Cancer Research. 61. 7785-7791. Dalmasso G, Cottrez F, Imbert V, Lagadec P, Peyron JF, Rampal P, Czerucka D, Groux H. Saccharomyces boulardii Inhibits Inflammatory Bowel Disease by Trapping T Cells in Mesenteric Lymph Nodes. Gastroenterology. 2006, 131, 1812-1825.
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| Home | Top of Page | Publications | |
| Team leader | ||||||
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| peyron@unice.fr | ||||||
| Researcher | ||||||
 J.F.
PEYRON |
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| V.
IMBERT |
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| D.
MARY |
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| Clinical researcher | ||||||
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| E.
GRIESSINGER |
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| M.
NEBOUT |
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| Etudiant | ||||||
| M.
POIREE |
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