CONTACT

Mathieu Gabut
Principal investigator

mathieu.gabut@inserm.fr

+33 469 856 092

Cancer Research Center of Lyon.
Inserm U1052, CNRS 5286
Cheney A building, 4th floor
Centre Leon Berard
28 rue Laennec
69008 LYON
FRANCE

GABUT Mathieu
Chef d'équipe, CRCN Inserm
mathieu.gabut@inserm.fr


Curriculum vitae

DURAND Sébastien

Chercheur CRCN Inserm
sebastien.durand@inserm.fr

DUCRAY François

Neuro-oncologue PUPH, HCL
francois.ducray@chu-lyon.fr

MEYRONET David

Neuro-pathologiste MCU-PH, HCL
david.meyronet@chu-lyon.fr

BARRITAULT Marc

Assistant hopitalo-universitaire, HCL
marc.barritault@chu-lyon.fr

BOURDELAIS Fleur
Ingénieur d'étude CLB
fleur.bourdelais@lyon.unicancer.fr
ISAAC Caroline

Assistante Ingénieur
caroline.isaac@lyon.unicancer.fr

BERABEZ Nabila
Etudiante en thèse UCBL
nabila.berabez@lyon.unicancer.fr
BENNYCHEN Bigitha
ERASMUS student
University of Leicester UK
GENTAZ Pauline
Etudiante M2 recherche Cancérologie 2.0
PICART Thiébaud
Neurochirurgien
Etudiant en M2 recherche UCBL
DIOT Thomas
Etudiant M2 bioinformatique UCBL
Voir les objectifs et projets Voir les publications
Collaborations
Corinne Augé-Gouillou, University of Tours (Tours, France) (link)
Alexandra Benchoua, iSTEM (Paris, France) (link)
Yohann Couté, CEA (Grenoble, France) (link)
Jean-Jacques DIAZ, CRCL (Lyon, France) (link)
Didier Frappaz, iHOPE (Lyon, France)
Jérôme Honnorat, Neuromyognene Institute (Lyon, France) (link)
Vincent Lacroix, LBBME (Lyon, France) (link)
Iouri Motorine, IMOPA - Lorraine University (Nancy, France) (link)
Olivier Namy, I2BC (Paris, France) (link)
Claude Pasquier, I3S (Nice, France) (link)
Jean-Paul Rieux, Institut Lumière Matière UCBL (Lyon, France) (link)
Thierry Virolle, iBV (Nice, France) (link)

Award
2012
Lap-Chee Tsui Publication Award from the Canadian Institute for Health Research (CIHR).

Funding

ATIP-AVENIR Program 2014-2018





SCIENTIFIC AND MEDICAL CONTEXT

Stem cells play a key role during development and in the homeostasis of adult tissues. Embryonic stem cells (ESC) have the unique capacities to self-renew while remaining pluripotent to generate all the cell types that constitute embryos. Along with these physiological contextes conserved accross evolution, additional cell types presentent similar properties in the context of pathologies, including cancers.
Indeed, cancer stem cells (CSC) have been identified in leukemias and in different types of solid tumors, including primary brain tumors. CSCs also present self-renewal and multipotency properties, and their enhanced plasticity contributes to intra-tumoral heterogeneity, resistance to treatments and tumor relapse.


In this context, our team combines different approaches including transcriptomics, cellular biology, biochemistry and biophysics to better characterize the emerging importance of post-transcriptional gene expression mechanisms in the control of the intrinsic properties of ESCs and of CSCs responsible for pediatric (medulloblastomas) and adult (glioblastomas) brain tumors.

PROJECT

Recent publications revealed that different post-transcriptional mechanisms play key roles in controlling stem cell fate, together with epigenetic and transcriptional regulations.
Firstly, we established that alternative splicing is regulated in murine and human ESCs and induced pluripotent stem cells (iPSC) to coordinate splicing programs that define the naive and pluripotent identity of stem cells (Gabut et al. Cell. 2011) (Han et al. Nature. 2013).
Recent data suggest that the translation machinery, the ribosomes, also plays an important and direct role in controlling gene expression in stem cells. Moreover, the molecular composition of ribosomes can be modulated in specific contexts, leading to the concept of specialized ribosomes which proposes that cells express different types of ribosomes adapted to their translation needs, including in pathological contexts such as cancer cells.
We hypothesize that stem cell plasticity is controlled by a coordinated regulation of the diversity of both the transcriptome (including by alternative splicing) and the machinery that translate it into a proteome: the ribosomes.

In this context, our objectives are to better characterize the role of alternative splicing and of the plasticity of ribosomes in the regulation of the molecular drivers of ESC and CSC identity maintenance. More precisely, our research aims at:

1- defining the function of splicing programs expressed in ESCs and CSCs for the maintenance of their pluripotency/multipotency and self-renewal.
2- identifying factors and signalling pathways that coordinate the regulation of these splicing programs in stem cells.
3- demonstrating that ESCs express specialized ribosomes and characterizing their role for translation control and pluripotent identity maintenance.
4- establishing the impact of translation control for ESC homeostasis and CSC tumorigenic properties.

 

LAB News (link)

Alumni. (link)

 

PUBLICATIONS

2016

Durand S, Franks T, Lykke-Andersen J: “Hyperphosphorylation amplifies UPF1 activity to resolve stalls in nonsense-mediated mRNA decay”. Nat Comm. 2016. 7:12434 (PMID: 27511142)

2015

Mocquet V, Durand S, Jalinot P: “How Retroviruses Escape the Nonsense-Mediated mRNA Decay?" AIDS research and human retroviruses, 2015. (PMID: 26066561)

Toma KG, Rebbapragada I, Durand S* and Lykke-Andersen J*: “Identification of 3’UTR Elements that Inhibit Nonsense-Mediated Decay” RNA 2015. (5):887-97. (PMID: 25805855)

Ruiz S, Lopez-Contreras AJ, Gabut M, Marion RM, Gutierrez-Martinez P, Bua S, Ramirez O, Olalde I, Rodrigo-Perez S, Li H, Marques-Bonet T, Serrano M, Blasco MA, Batada NN, Fernandez-Capetillo O. "Limiting replication stress during somatic cell reprogramming reduces genomic instability in induced pluripotent stem cells." Nat Commun. 2015. 6:8036. (PMID: 26292731)

2013

Han H, Irimia M, Ross PJ, Sung HK, Alipanahi B, David L, Golipour A, Gabut M, Michael IP, Nachman EN, Wang E, Trcka D, Thompson T, O'Hanlon D, Slobodeniuc V, Barbosa-Morais NL, Burge CB, Moffat J, Frey BJ, Nagy A, Ellis J, Wrana JL, Blencowe BJ. MBNL proteins repress ES-cell-specific alternative splicing and reprogramming. Nature. 2013. 498(7453):241-5. [PMID: 23739326

Durand S and Lykke-Andersen J: “Nonsense-mediated mRNA decay occurs during eIF4Fdependent translation in human cells”. Nat Struct Mol Biol., 2013. 20(6):702-9. (PMID: 23665580)  

2012

Gabut M. Pluripotence des cellules souches: quand l’épissage alternatif s’en mêle. Médecine Sciences. 2012. 28(4):372-4. [PMID: 22549864]

2011

Gabut M, Samavarchi-Tehrani P, Wang X, Slobodeniuc V, O’Hanlon D, et al. An Alternative Splicing Switch Regulates Embryonic Stem Cell Pluripotency and Reprogramming. Cell2011. 17(1):132-146 [PMID: 21924763]

Durand S and Lykke-Andersen J: “Nonsense-mediated mRNA decay”. Cell. 2011. 145(2):324-324.e2. (PMID: 21496649) 

2009

Calarco JA, Superina S, O'Hanlon D, Gabut M, Raj B, et al. Regulation of vertebrate nervous system alternative splicing and development by an SR-related protein. Cell2009. 138(5):898-910. [PMID: 19737518].

2008

Gabut M, Chaudhry S, Blencowe BJ. The splicing regulatory machinery. Cell2008. 133(1):192.e1. [PMID: 18394998]. 

Chavey C, Muhlbauer M, Bossard C, Freund A, Durand S, Jorgensen C, Jobin C, Lazennec G. “Interleukin-8 expression is regulated by histone deacetylases through the NF-{kappa}B pathway in breast cancer” Molecular Pharmacology. 2008 (PMID: 18669446)  

2007

Gabut M, Dejardin J, Tazi J, Soret J. The SR family proteins B52 and dASF/SF2 modulate development of the Drosophila visual system by regulating specific RNA targets. Mol Cell Biol2007. (8):3087-97. [PMID: 17283056].

Durand S, Cougot N, Mahuteau-Betzer F, Nguyen CH, Grierson DS, Bertrand E, Tazi J and Lejeune F “Inhibition of nonsense-mediated mRNA decay (NMD) by a novel chemical molecule reveals the dynamic of NMD factors in P-bodies”. Journal of Cell Biology, 2007 178(7):1145-1160 (PMID: 17893241)  

2006

Soret J, Gabut M, Tazi J. SR proteins as potential targets for therapy. Prog Mol Subcell Biol2006. 4:65-87. [PMID: 17076265].

2005

Soret J, Bakkour N, Maire S, Durand S, Zekri L, Gabut M, et al. Selective modification of alternative splicing by indole derivatives that target serine-arginine-rich protein splicing factors. PNAS2005. 102(24):8764-9. [PMID: 15939885].

Gabut M, Miné M, Marsac C, Brivet M, Tazi J, Soret J. The SR protein SC35 is responsible for aberrant splicing of the E1alpha pyruvate dehydrogenase mRNA in a case of mental retardation with lactic acidosis. Mol Cell Biol2005. (8):3286-94. [PMID: 15798212].

Soret J, Bakkour N, Maire S, Durand S, Zekri L, Gabut M, Fic W, Divita G, Rivalle C, Dauzonne D, Nguyen CH, Jeanteur P, Tazi J. “Selective modification of alternative splicing by indole derivatives that target serine-arginine-rich protein splicing factors”. PNAS, 2005;102(24):8764-9 (PMID: 15939885)

Tazi J, Durand S, Jeanteur P: “The spliceosome: a novel multi-faceted target for therapy”. Trends in Biochemical Sciences, 2005 Aug; 30(8):469-78 (PMID: 16009556)

2004

Freund A, Jolivel V, Durand S, Kersual N, Chalbos D, Chavey C, Vignon F, Lazennec G “Mechanisms underlying differential expression of interleukin-8 in breast cancer cells”. Oncogene, 2004 ;23(36):6105-14 (PMID: 1208657)

2003

Soret J*, Gabut M*, Dupon C, Kohlhagen G, Stévenin J, et al. Altered serine/arginine-rich protein phosphorylation and exonic enhancer-dependent splicing in Mammalian cells lacking topoisomerase I. Cancer Res2003. 63(23):8203-11. [PMID: 14678976]. (* co-first authors)

Bantignies F, Grimaud C, Lavrov S, Gabut M, Cavalli G. Inheritance of Polycomb-dependent chromosomal interactions in Drosophila. Genes Dev2003. 17(19):2406-20. [PMID: 14522946].

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