lkb1 - p53 & cell plasticity - grenoble · lkb1 - p53 & cell plasticity group leader...

LKB1 - p53 & CELL PLASTICITY Group leader Chantal THIBERT (CR1, CNRS) Lab members Sakina TORCH, MCF (UGA) Anthony LUCAS, IE-2 st year PhD student (INSERM, UGA) Marie MEVEL, M2 student (ISPB, Lyon) Lab alumni Anca Radu, PhD student (UGA, 2014-2018) Maud Schweitzer, Tech student (ESTBB, Lyon, 2018) Matthieu Aguilera, L3 student (UGA, 2018) Claudie COMEAU, M1 student (Sherbrook University, Quebec, 2017) Mélissa BOUZAR, M1 student (UGA, 2017) è We are exploring the metabolic regulations by LKB1 and p53 in development and cancer. Cells adapt constantly their metabolism to their environment through signalling pathways that act as biosensors of nutrient availability. The kinase tumour suppressor LKB1 and its downstream kinase substrate AMPK are sensors of ATP levels. Under metabolic stress, they refurnish cell energy by activating ATP-generating and inhibiting ATP-consuming processes such as mTOR. Using genetically engineered mouse models of spatio-temporal inactivation of Lkb1, we have recently uncovered that Lkb1/AMPK governs cell fate by connecting mTOR activity to pyruvate-alanine cycling and glutamate- glutamine conversion. We also highlighted that Lkb1 prevents oxidative DNA damages and p53 activation, a necessary process for correct cell fate both in vitro and in vivo. We are currently exploring the underlying molecular mechanisms of LKB1-p53 crosstalk to better understand how LKB1 signalling under metabolic stress impacts p53 non-transcriptional, transcriptional and epigenetics activities in normal and pathological conditions. Our group belongs to Pr. Hainaut lab at the Institute for Advanced Biosciences since 2016. We are member of the French network CREST-NET on neural crest stem cells. Recent publications: - Radu A * , Torch S * , Fauvelle F, Pernet-Gallay K, Blervaque R, Lucas A, Delmas V, Schlattner U, Tricaud N, Lafenechère L, Hainaut P, Tricaud N, Pingault V, Bondurand N, Bardeesy N, Larue L, Thibert C § and Billaud M. § LKB1 specifies neural crest cell lineages through pyruvate-alanine cycling. In revision at Science Advances. * Co-first; § co-senior and co-corresponding. - Cordier-Bussat M, Thibert C, Sujobert P, Fontaine E and Billaud M. Même l’effet Warburg est oxydable : coopération métabolique et développement tumoral. médecine/sciences, 34:701-708. - Creuzet S *§ , Viallet J * , Ghawitian M, Torch S, Thélu J, Alrajeh M, Radu AG, Bouvard D, Costagliola F, Le Borgne M, Buchet-Poyau K, Aznar N, Buschlen S, Hosoya H, Thibert C § and Billaud M § (2016) LKB1 signaling in cephalic neural crest cells is essential for vertebrate head development. Dev Biol. 428:283-296 * Co-first; § co-corresponding authors. - Mille F + , Thibert C + , Fombonne J, Rama N, Guix C, Hayashi H, Corset V, Reed J and Mehlen P. (2009) The Patched dependence receptor triggers apoptosis through a DRAL-caspase9 complex. Nat Cell Biol. 11:739-46 + Co-first. - Thibert C, Teillet MA, Lapointe F, Mazelin L, Le Douarin NM and Mehlen P. (2003) Inhibition of neuroepithelial Patched-induced apoptosis by Sonic hedgehog. Science, 301:843-846. Contact and information: Email: [email protected] Phone : +33 (0)4 76 54 95 75 Researchgate: https://www.researchgate.net/profile/Chantal_Thibert LKB1 Cell metabolism & cell fate: Cell models: Neural crest stem cells Lung tumor cells p53 ?

Upload: others

Post on 15-Aug-2020

4 views

Category:

Documents

0 download

Report

Download

Embed Size (px):

TRANSCRIPT

LKB1-p53&CELLPLASTICITY

Groupleader

ChantalTHIBERT(CR1,CNRS)

Labmembers

SakinaTORCH,MCF(UGA)AnthonyLUCAS,IE-2styearPhDstudent(INSERM,UGA)MarieMEVEL,M2student(ISPB,Lyon)

Labalumni

AncaRadu,PhDstudent(UGA,2014-2018)MaudSchweitzer,Techstudent(ESTBB,Lyon,2018)MatthieuAguilera,L3student(UGA,2018)ClaudieCOMEAU,M1student(SherbrookUniversity,Quebec,2017)MélissaBOUZAR,M1student(UGA,2017)

è We are exploring the metabolic regulations by LKB1 and p53 in development and cancer. Cellsadaptconstantlytheirmetabolismtotheirenvironmentthroughsignallingpathwaysthatactasbiosensors of nutrient availability. The kinase tumour suppressor LKB1 and its downstream kinasesubstrate AMPK are sensors of ATP levels. Under metabolic stress, they refurnish cell energy byactivatingATP-generatingand inhibitingATP-consumingprocessessuchasmTOR.Usinggeneticallyengineeredmousemodelsofspatio-temporalinactivationofLkb1,wehaverecentlyuncoveredthatLkb1/AMPKgovernscellfatebyconnectingmTORactivitytopyruvate-alaninecyclingandglutamate-glutamine conversion. We also highlighted that Lkb1 prevents oxidative DNA damages and p53activation,anecessaryprocessforcorrectcellfatebothinvitroandinvivo.WearecurrentlyexploringtheunderlyingmolecularmechanismsofLKB1-p53crosstalktobetterunderstandhowLKB1signallingunder metabolic stress impacts p53 non-transcriptional, transcriptional and

epigeneticsactivitiesinnormalandpathologicalconditions.OurgroupbelongstoPr.HainautlabattheInstituteforAdvancedBiosciencessince2016.We

arememberoftheFrenchnetworkCREST-NETonneuralcreststemcells.

Recent publications: -RaduA*,TorchS*,FauvelleF,Pernet-GallayK,BlervaqueR,LucasA,DelmasV,SchlattnerU,TricaudN,LafenechèreL,HainautP,TricaudN,PingaultV,BondurandN,BardeesyN,LarueL,ThibertC§andBillaudM.§LKB1specifiesneuralcrestcelllineagesthroughpyruvate-alaninecycling.InrevisionatScienceAdvances.*Co-first;§co-seniorandco-corresponding.- Cordier-Bussat M, Thibert C, Sujobert P, Fontaine E and Billaud M. Même l’effet Warburg est oxydable: coopération métabolique etdéveloppementtumoral.médecine/sciences,34:701-708.-CreuzetS*§,VialletJ*,GhawitianM,TorchS,ThéluJ,AlrajehM,RaduAG,BouvardD,CostagliolaF,LeBorgneM,Buchet-PoyauK,AznarN,BuschlenS,HosoyaH,ThibertC§andBillaudM§(2016)LKB1signalingincephalicneuralcrestcellsisessentialforvertebrateheaddevelopment.DevBiol.428:283-296*Co-first;§co-correspondingauthors.-MilleF+,ThibertC+,FombonneJ,RamaN,GuixC,HayashiH,CorsetV,ReedJandMehlenP.(2009)ThePatcheddependencereceptortriggersapoptosisthroughaDRAL-caspase9complex.NatCellBiol.11:739-46+Co-first.-ThibertC,TeilletMA,LapointeF,MazelinL,LeDouarinNMandMehlenP.(2003)InhibitionofneuroepithelialPatched-inducedapoptosisbySonichedgehog.Science,301:843-846.

Contact and information: Email: [email protected] Phone : +33 (0)4 76 54 95 75 Researchgate: https://www.researchgate.net/profile/Chantal_Thibert

LKB1

Cellmetabolism&cellfate:

Cellmodels:

Neuralcreststemcells

Lungtumorcells

p53

RIP2-mediated LKB1 deletion causes axon degeneration in ...dmm.biologists.org/content/dmm/4/2/193.full.pdf · limb paralysis To generate mice lacking LKB1 in the mid and ventral brain,

Peutz-Jeghers Syndrome (PJS) and LKB1

The MDM2/MDMX-p53 Antagonist PM2 Radiosensitizes Wild … · performed on 3D multicellular tumor spheroids, using wt p53, p53, and mutant p53 cancer cells as described in the/ Supplementary

progression via CCL2-dependent macrophage LKB1 loss …€¦ · LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitment Christopher G. Peña, 1,2

LKB1 and AMPK and the cancer-metabolism link - BioMed Central