ecole doctorale « medicament - L`Institut de Formation Doctorale

ED BIO SORBONNE PARIS CITE
Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2017-2018
Renseignements relatifs à l’Unité de Recherche :
Label et intitulé : Institut Jacques MONOD – UMR 7592, CNRS, Université Paris DIDEROT – PARIS 7
Nom et prénom du Directeur : BALDACCI Giuseppe
Téléphone :
01 57 27 81 39
Télécopie : 01 57 27 81 35
Courriel: [email protected]
Renseignements relatifs à l’Equipe :
Nom de l’Equipe d’Accueil : Pathologies de la Réplication de l'ADN
Nom et prénom du responsable : BALDACCI Giuseppe
Qualité du responsable : Professeur Université Paris DIDEROT – PARIS 7
Téléphone :
01 57 27 81 39
Télécopie : 01 57 27 81 35
Courriel : [email protected]
Renseignements relatifs au sujet de thèse :
Nom et prénom du Directeur de thèse (HDR) : CADORET Jean-Charles (HDR) et FAUCHEREAU
Fabien (co-directeur)
Qualité : Maître de Conférences Paris 7
Téléphone :
01 57 27 80 74
Télécopie : 01 57 27 81 35
Courriel : [email protected], [email protected]
Titre du sujet proposé :
Etude moléculaire des mécanismes d'action d'inhibiteurs de CDK4 et CDK6 sur les carcinomes
adrénocorticaux / Molecular study of the mechanisms of action of CDK4 and CDK6 inhibitors on
adrenocortical carcinomas.
Département (cocher le département correspondant au sujet de thèse qui n’est pas obligatoirement le
vôtre) :
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
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Biologie Cellulaire et Moléculaire, Physiologie et Physiopathologie
Immunologie
Développement Génétique Neurobiologie et Vieillissement
Infectiologie, Microbiologie
Summary: This project will focus on the impact of drugs (identified through bioinformatic analyses of
genomic data) on cellular models of adrenocortical carcinomas (ACCs). The student will test the impact
of drugs (either individually or in combination) on cell viability, migration, invasiveness, autophagy and
hormone secretion, as well as through cellular and in vivo approaches. The student will also perform
bioinformatic analyses on genomic data available on The Cancer Genome Atlas database, in order to
define DNA replication-based groups of cancers.
Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2017-2018
Nom, prénom du directeur de l'unité de recherche : BALDACCI Giuseppe
Numéro de l'unité de recherche (et établissement de rattachement) : Institut Jacques MONOD UMR
7592 CNRS Université Paris DIDEROT – Paris 7.
Nom, prénom du responsable de l'équipe d'accueil (EAD) : BALDACCI Giuseppe
Nom, prénom du directeur de thèse : CADORET Jean-Charles, FAUCHEREAU Fabien (co-directeur)
Titre du sujet de thèse proposé : Molecular study of the mechanisms of action of CDK4 and CDK6
inhibitors on adrenocortical carcinomas
Citer 5 mots clés : cancer, DNA replication, therapeutical targets, drug combination,
Bioinformatics
Candidat pressenti :
 OUI

NON
Contenu scientifique du programme de la thèse
Adrenocortical carcinomas (ACCs) are deadly cancers with limited opportunities of treatment. We
studied transcriptomic data generated from adrenocortical tumors by "The Cancer Genome Atlas"
consortium (TCGA). Our study was focused on the expression levels of 136 genes involved in the G1/S
phase transition and DNA replication. Correlation of mRNA levels with clinical data showed that high
gene expression of CDK6 was associated with a short time to relapse and death. Thus we tested the
impact of CDK4 and CDK6 inhibitors (namely palbociclib and ribociclib) on cell viability of the NCI-H295R
and SW-13 cell lines, which were derived from ACCs. Both drugs decreased cell viability of the ACCderived cell lines and are possible candidates for clinical testing. Reduction of cell viability was
associated with aberrant cell cycle and senescence. Our observations also prompt us to explore
palbociclib effect on epithelio-mesenchymal transition (EMT), and autophagy.
Since previous cell cycle analyses suggested abnormal DNA synthesis during S-phase after
treatments, a precise profile of DNA replication timing-program will be generated on treated cells. The
PhD student will also study the impact of palbociclib and ribociclib on EMT by assessing cellular
adherence, migration and invasiveness of NCI-H295R and SW-13 cells. He/she will test their impact on
cellular pathways that are involved in EMT (-catenin, cadherins and vimentin). Since autophagy is
involved in several cellular processes that may either facilitate or suppress tumorigenesis, including
secretion of steroid hormones, the student will measure autophagy after treatments with either
palbociclib or ribociclib. Hormone secretion will also be assayed on hormone-secreting NCI-H295R cells.
Second, the student will test on NCI-H295R and SW-13 cell lines the possible synergic
interactions between ribociclib or palbociclib and other anti-cancer drugs. Such combinations can
potentiate the effects of drugs and reduce the concentration needed to reach therapeutic benefits. After
treatment of cells with combined drugs, their impact on cell viability will be tested. Further analyses will
be performed on mouse xenograft models, in collaboration with other groups.
Finally, the bioinformatic approach mentioned above brought fresh perspectives to our research
and we will extend these analyses to all the cancers studied by TCGA. To achieve this, clusters of
cancers will be defined, based on mRNA levels of genes involved in DNA replication (such clusters may
include cancers affecting different tissues). Clinical (time of relapse-free survival, or overall survival) and
molecular (mutation rate, chromosomal abnormalities) features between groups will then be compared.
This approach will result in a more integrative perspective of DNA replication in cancer. The scientific
staff of our research group will teach to the student the bioinformatic tools needed for this project.
Indiquez les cinq meilleures publications récentes de l’équipe :
1. Fauchereau F, Shalev S, Chervinsky E, Beck-Fruchter R, Legois B, Fellous M, Caburet S, Veitia RA. A nonsense MCM9 mutation in a familial case of primary ovarian insufficiency. Clin Genet. 2016 May;89(5):603-7.
2. Hadjadj D, Denecker T, Maric C, Fauchereau F, Baldacci G, Cadoret JC. Characterization of the replication
timing program of 6 human model cell lines. Genom Data. 2016 Jul 15;9:113-7.
3. Baldacci G, Hoffmann JS, Cadoret JC. Impact of the DNA polymerase Theta on the DNA replication program.
Genom Data. 2014 Dec 5;3:90-3.
4. Maric C, Bénard M. Replication forks reverse at high frequency upon replication stress in Physarum
polycephalum. Chromosoma. 2014 Dec;123(6):577-85.
5. Fernandez-Vidal A,* Guitton-Sert L,* Cadoret JC,* Drac M, Schwob E, Baldacci G, Cazaux C, Hoffmann JS. A
role for DNA polymerase θ in the timing of DNA replication. Nat Commun. 2014 Jul 3;5:4285. (* co-first authors)