Co direction d'équipe :

Germain GILLET
04 69 16 66 56

04 78 78 29 03

Cheney D - 5ème étage
Centre Léon Bérard
ALLIOLI Nathalie
BOREL Stéphane
Duong Minh Quang
Gillet Germain

Co-chef d'équipe
Professeur des universités (UCBL)
GONZALO Philippe

Professeur et Praticien hospitalier

PhD student
LOHEZ Olivier
LOPEZ Jonathan
PONCET Delphine

Co-chef d'équipe
DR2 Inserm
ZHAO Yajie
Voir les objectifs et projets Voir les publications




Les mécanismes impliqués dans la progression tumorale et l’apparition des métastases restent encore mal connus. La Transition Epithélio-Mésenchymateuse (EMT) est un programme de trans-différenciation embryonnaire fréquemment réactivé lors de l’apparition des métastases. L’EMT favorise en effet la migration des cellules et l’invasion tumorale. L’objectif général de ce projet est d’identifier les mécanismes qui concourent à la réactivation de l’EMT et à la progression tumorale dans la tumorigenèse mammaire. A l’aide de modèles animaux comme la souris et le zebrafish, nous focalisons nos études autour de trois axes:

1- la voie de signalisation du TGFbeta,

2- les perturbations du métabolisme énergétique et leurs conséquences dans le développement tumoral,

3- le contrôle des flux calciques par les membres de la famille Bcl2.

Metabolism and tumor progression group

 Metabolism and tumor progression group :

Three main axis are developped in the group:

1- the TGFß pathway and its role in EMT.

2- the perturbations of glucose metabolism that characterize cancer cells and their consequences for tumor progression.

3- the regulation of calcium fluxes by the Bcl-2 family members.

Stomal Immune Interactions in Cancer

Group members
Ana Hennino,PhD CRCN Inserm, Group Leader,
Christelle de la Fouchardière, MD, CLB, oncologist
Pia Gamradt, PhD post doc
Zhichong Wu, MD surgeon, PhD student
Sophie Bachy, Engineer, Lab manager
Kevin Thierry, Master student



Most of the therapeutic approaches have targeted tumor cells themselves and, until recently, have largely ignored the very obvious stroma/desmoplastic reaction that is a characteristic feature of several human cancer ie pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer related death in the industrialized world it is predicted to become the 2nd leading cause of cancer related death by 2030. Since few years the contribution of this massive stroma has emerged as a novel actor and contributor of pancreatic tumor initiation and progression. This abundant stromal reaction usually surrounds islands of cancer cells, and accounts for 50–80% of tumor volume. It is now well established that PDAC is associated with a profound immune suppression and that this phenomenon is largely due to the fact that the effective anti-tumoral immune response is unable to "reach" the tumoral zone and remains "physically and functionally" restricted to tumor surrounding microenvironment. Moreover, the high density of the pancreatic associated stroma further impair drug delivery and provides mechanical stiffness. We have recently demonstrated that big-h3/TGFbi (Transforming growth factor-b-induced gene product), an ECM protein plays an important role in the stiffness modulation of microenvironment in PDAC. We also showed that this protein has immune-suppressive properties in autoimmune context. big-h3 is expressed in a wide variety of tissues, binds to type I, II, and IV collagens, as well as he proteoglycans, biglycan and decorin and plays important roles in cell-to-cell, cell-to-collagen, and cell-to-matrix interactions. 
We explore mainly:
-The role of the mechanical changes in the emergence of the pitfalls of the immune-surveillance at the onset of neoplasia lesions by acinar to ductal metaplasia.
-The relationship between the mechanical stiffness generated by Cancer Associated and immune cells present within the tumor stroma and the immune-escape.
-The role of depleting extracellular matrix protein, in the mechanical tension release within the tumor and impact on the immune-suppression (with a special focus on CD8+T cells and macrophages) in cancer.



N. Popgeorgiev, L. Jabbour & G. Gillet (2018) Subcellular localization and dynamics of the Bcl-2 family of proteins. Front. Cell Dev. Biol. doi: 10.3389/fcell.2018.00013
N. Popgeorgiev, B. Bonneau, J. Prudent, & G. Gillet (2018) Control of Programmed Cell Death During Zebrafish Embryonic Development. In Recent Advances in Zebrafish Researches  Yusuf Bozkurt ed. IntechOpen, pp189-210
 A. Nougarede, N. Popgeorgiev, L. Kassem, S. Omarjee, S. Borel, I. Mikaelian, J. Lopez, R. Gadet, O. Marcillat, I. Treilleux, B.O.Villoutreix, R. Rimokh & G. Gillet (2018) Breast cancer targeting through inhibition of the endoplasmic reticulum-based apoptosis regulator Nrh/BCL2L10. Cancer Res. 78:1404-17


Rouvière O, Dagonneau T, Cros F, Bratan F, Roche L, Mège-Lechevallier F, Ruffion A, Crouzet S, Colombel M, Rabilloud M. Diagnostic value and relative weight of sequence-specific magnetic resonance features in characterizing clinically significant prostate cancers. PLoS One. 2017 Jun 9;12(6):e0178901. doi: 10.1371/journal.pone.0178901. eCollection 2017.

Gherardi S, Ripoche D, Mikaelian I, Chanal M, Teinturier R, Goehrig D, Cordier-Bussat M, Zhang CX, Hennino A, Bertolino P. Menin regulates Inhbb expression through an Akt/Ezh2-mediated H3K27 histone modification. ​Biochim Biophys Acta. 2017 Apr;1860(4):427-437. doi: 10.1016/j.bbagrm.2017.02.003. Epub 2017 Feb 12.


Prudent J, Popgeorgiev N, Gadet R, Deygas M, Rimokh R, Gillet G. Mitochondrial Ca2+ uptake controls actin cytoskeleton dynamics during cell migration. Sci Rep. 2016 Nov 9;6:36570. doi: 10.1038/srep36570.

​​​​​Goulvent T, Ray-Coquard I, Borel S, Haddad V, Devouassoux-Shisheboran M, Vacher-Lavenu MC, Pujade-Laurraine E, Savina A, Maillet D, Gillet G, Treilleux I, Rimokh R. DICER1 and FOXL2 mutations in ovarian sex cord-stromal tumours: aGINECO Group study. Histopathology. 2016 Jan;68(2):279-85.


Prudent J, Popgeorgiev N, Bonneau B, Gillet G. Bcl-2 proteins, cell migration and embryonic development: lessons from zebrafish. Cell Death Dis. 2015 Oct 15;6:e1910.

Ruff M, Leyme A, Le Cann F, Bonnier D, Le Seyec J, Chesnel F, Fattet L, Rimokh R, Baffet G, Théret N. The Disintegrin and Metalloprotease ADAM12 Is Associated with TGF-β-Induced Epithelial to Mesenchymal Transition. PLoS One. 2015 Sep 25;10(9):e0139179.

Kassem L, Deygas M, Fattet L, Lopez J, Goulvent T, Lavergne E, Chabaud S,Carrabin N, Chopin N, Bachelot T, Gillet G, Treilleux I, Rimokh R. TIF1γ interferes with TGFβ1/SMAD4 signaling to promote poor outcome in operable breast cancer patients. BMC Cancer. 2015 Jun 4;15:453.

François CM, Wargnier R, Petit F, Goulvent T, Rimokh R, Treilleux I, Ray-Coquard I, Zazzu V, Cohen-Tannoudji J, Guigon CJ. 17β-estradiol inhibits spreading of metastatic cells from granulosa cell tumors through a non-genomic mechanism involving GPER1. Carcinogenesis. 2015 May;36(5):564-73.

Edmond V, Dufour F, Poiroux G, Shoji K, Malleter M, Fouqué A, Tauzin S,Rimokh R, Sergent O, Penna A, Dupuy A, Levade T, Theret N, Micheau O, Ségui B, Legembre P. Downregulation of ceramide synthase-6 during epithelial-to-mesenchymal transition reduces plasma membrane fluidity and cancer cell motility. Oncogene. 2015 Feb 19;34(8):996-1005.


Biarc J, Gonzalo P, Mikaelian I, Fattet L, Deygas M, Gillet G, Lemoine J,Rimokh R. Combination of a discovery LC-MS/MS analysis and a label-free quantification for the characterization of an epithelial-mesenchymal transition signature. J Proteomics. 2014 Oct 14;110:183-94.

Vlaeminck-Guillem V, Gillet G, Rimokh R. SRC: marker or actor in prostate cancer aggressiveness. Front Oncol. 2014 Aug 18;4:222.

Dardenne E, Polay Espinoza M, Fattet L, Germann S, Lambert MP, Neil H, Zonta E, Mortada H, Gratadou L, Deygas M, Chakrama FZ, Samaan S, Desmet FO, Tranchevent LC, Dutertre M, Rimokh R, Bourgeois CF, Auboeuf D. RNA helicases DDX5 and DDX17 dynamically orchestrate transcription, miRNA, and splicing programs in cell differentiation. Cell Rep.2014 Jun 26;7(6):1900-13.

Bonneau B, Nougarède A, Prudent J, Popgeorgiev N, Peyriéras N, Rimokh R, Gillet G. The Bcl-2 homolog Nrz inhibits binding of IP3 to its receptor to control calcium signaling during zebrafish epiboly. Sci Signal. 2014 Feb11;7(312):ra14.

Prudent J, Gillet G, Popgeorgiev N. Nrz but not zBcl-xL antagonizes Bcl-wav pro-apoptotic activity in zebrafish. Commun Integr Biol. 2014 Jan 1;7(1):e28008.

Maillet D, Goulvent T, Rimokh R, Vacher-Lavenu MC, Pautier P, Alexandre J, Pujade-Laurraine E, Devouassoux-Shisheboran M, Treilleux I, Ray-Coquard I, Savina A. Impact of a second opinion using expression and molecular analysis of FOXL2 for sex cord-stromal tumors. A study of the GINECO group & the TMRO network. Gynecol Oncol. 2014 Jan;132(1):181-7.


Mikaelian I, Malek M, Viallet J, Garcia A, Girard A, Hesling C, Gillet G, Gonzalo P, Rimokh R and Billaud M. A siRNA screen identifies a role for mTORC1 in the maintenance of the epithelial integrity. Cancer Res2013;73(22):6621-31.

Prudent J, Popgeorgiev N, Bonneau B, Thibaut J, Gadet R, Lopez J, Gonzalo P, Rimokh R, Manon S, Houart C, Herbomel P, Aouacheria A and Gillet G. Bcl-wav and the mitochondrial calcium uniporter drive gastrula morphogenesis in zebrafish. Nat Commun 2013;4:2330. doi: 10.1038/ncomms3330. 

Fattet L, Ay AS, Bonneau B, Jallades L, Mikaelian I, Treilleux I, Gillet G, Hesling C, Rimokh R. TIF1γ requires sumoylation to exert its repressive activity on TGFβ signaling.  J Cell Sci 2013; 126(Pt 16):3713-23. 

Ballesta A, Lopez J, Popgeorgiev N, Gonzalo P, Doumic M, Gillet G. Data-driven modeling of SRC control on the mitochondrial pathway of apoptosis: implication for anticancer therapy optimization. PLoS Comput Biol 2013;9(4):e1003011. doi: 10.1371/journal.pcbi.1003011.

Bonneau B, Prudent J, Popgeorgiev N, Gillet G. Non-apoptotic roles of Bcl-2 family: the calcium connection. Biochem Biophys Acta 2013;1833(7):1755-65.

Dibenedetto S, Cluet D, Stebe PN, Baumle V, Leault J, Terreux R, Bickle M, de Chassey B, Mikaelian I, Colas P, Spichty M, Zoli M, Rudkin BB. Calcineurin A vs NS5A-TP2/HDDC2: a case study of site-directed low-frequency random mutagenesis for dissecting target specificity of peptide aptamers. Mol Cell Proteomics 2013;12(7):1939-52.

Deshiere A, Duchemin-Pelletier E, Spreux E, Ciais D, Combes F, Vandenbrouck Y, Coute Y, Mikaelian I, Giusiano S, Charpin C, Cochet C, Filhol O. Unbalanced expression of CK2 kinase subunits is sufficient to drive epithelial-to-mesenchymal transition by Snail1 induction. Oncogene 2013;32(11):1373-83.

Hesling C, Lopez J, Fattet L, Gonzalo P, Treilleux I, Blanchard D, Losson R, Goffin V, Pigat N, Puisieux A, Mikaelian I, Gillet G, Rimokh R. Tif1γ is essential for the terminal differentiation of mammary alveolar epithelial cells and for lactation through SMAD4 inhibition. Development 2013;140(1):167-75.


Andrieux G, Fattet L, Le Borgne M, Rimokh R, Théret N. Dynamic regulation of Tgf-B signaling by Tif1γ: a computational approach. PLoS One 2012; 7(3):e33761. doi: 10.1371/journal.pone.0033761.

Lopez J, Hesling C, Prudent J, Popgeorgiev N, Gadet R, Mikaelian I, Rimokh R, Gillet G, Gonzalo P. Src tyrosine kinase inhibits apoptosis through the Erk1/2-dependent degradation of the death accelerator Bik.Cell Death Differ 2012;19(9):1459-69.

Malek M, Guillaumot P, Huber AL, Lebeau J, Pétrilli V, Kfoury A, Mikaelian I, Renno T, Manié SN. LAMTOR1 depletion induces p53-dependent apoptosis via aberrant lysosomal activation. Cell Death Dis2012 ;19;3:e300.

Thibaut J, Mérieux Y, Rigal D, Gillet G. A novel assay for the detection of anti-human platelet antigen antibodies (HPA-1a) based on peptide aptamer technology. Haematologica 2012;97(5):696–704.

Valero JG, Cornut-Thibaut A, Jugé R, Debaud A-L, Giménez D, Gillet G, Bonnefoy-Bérard N, Salgado J, Salles G, Aouacheria A. µ-Calpain conversion of antiapoptotic Bfl-1 (BCL2A1) into a prodeath factor reveals two distinct alpha-helices inducing mitochondria-mediated apoptosis. PLoS One2012;7(6):e38620. doi: 10.1371/journal.pone.0038620.

Vendrell JA, Thollet A, Nguyen NT, Ghayad SE, Vinot S, Bièche I, Grisard E, Josserand V, Coll JL, Roux P, Corbo L, Treilleux I, Rimokh R, Cohen PA. ZNF217 is a marker of poor prognosis in breast cancer that drives epithelial-mesenchymal transition and invasion. Cancer Res 2012;72(14):3593-606.


Bonneau B, Popgeorgiev N, Prudent, Gillet G. Cytoskeleton dynamics in early zebrafish development: a matter of phosphorylation ? Bioarchitecture 2011;1(5):216-20.

Popgeorgiev N, Prudent J, Bonneau B, Gillet G. The yolk cell of the zebrafish blastula harbors functional apoptosis machinery. Communicative Integr Biol 2011;4(5):549-51.

Hesling C, Fattet L, Teyre G, Jury D, Gonzalo P, Lopez J, Vanbelle C, Morel AP, Gillet G, Mikaelian I, Rimokh R. Antagonistic regulation of EMT by TIF1γ and Smad4 in mammary epithelial cells. EMBO Rep2011;12(7):665-72.

Guillemin Y, Cornut-Thibaut A, Gillet G, Penin F, Aouacheria A. Characterization of unique signature sequences in the divergent maternal Protein BCL2L10. Mol Biol Evol 2011;28(12):3271-83.

Popgeorgiev N, Bonneau B, Ferri KF, Prudent J, Thibaut J, Gillet G. The apoptotic regulator Nrz controls cytoskeletal dynamics via the regulation of Ca(2+) trafficking in the zebrafish blastula. Dev Cell2011;20(5):663-76.

Garcia AI, Buisson M, Bertrand P, Rimokh R, Rouleau E, Lopez BS, Lidereau R, Mikaélian I, Mazoyer S. Down-regulation of BRCA1 expression by miR-146a and miR-146b-5p in triple negative sporadic breast cancers. EMBO Mol Med 2011;3(5):279-90.

Morello LG*, Hesling C*, Coltri P, Castilho BA, Rimokh R, Zanchin NI. The NIP7 protein is required for accurate pre-rRNA processing in human cells. Nucleic Ac Res 2011;39(2):648-65. *Equal contribution

Valero JG, Sancey L, Kucharczak J, Guillemin Y, Gimenez D, Prudent J, Gillet G, Salgado J, Coll JL, Aouacheria A. Bax-derived membrane-active peptides act as potent and direct inducers of apoptosis in cancer cells. J Cell Sci 2011;124(Pt 4):556-64.

Copyright 2011. CRCL