CONTACT

Alain PUISIEUX
alain.puisieux@lyon.unicancer.fr

See Pr. Puisieux's Biography

Cheney D - 2nd floor
Centre Léon Bérard
28 rue Laennec
69373 Lyon Cedex 08
France
ANGILERI Francesca

Post-doctoral researcher

francesca.angileri@lyon.unicancer.fr

BENHASSOUN Rahma
CHASSOT Christelle

Lab technician, Centre Léon Bérard

christelle.chassot@lyon.unicancer.fr

DE BLANDER Hadrien
DEVOUASSOUX-SHISHEBORAN Mojgan

Professor and Hospital Practitioner, Université Lyon 1 / Hospices Civils de Lyon

mojgan.devouassoux@chu-lyon.fr

FAUVET Frédérique

Engineer, Centre Léon Bérard

frederique.fauvet@lyon.unicancer.fr

LACHUER Joël

Professor, Université Lyon 1

joel.lachuer@univ-lyon1.fr

MARTINEZ Pierre

Senior researcher (CRCN), Inserm

pierre.martinez@lyon.unicancer.fr

MOREL Anne-Pierre

Senior researcher, Centre Léon Bérard

annepierre.morel@lyon.unciacner.fr

MOYRET-LALLE Caroline

Professor, Université Lyon 1

caroline.moyret-lalle@lyon.unicancer.fr

OUZOUNOVA Maria

Senior researcher (CRCN), CNRS

maria.ouzounova@lyon.unicancer.fr

PAYEN-GAY Léa
Professor and Hospital Practitioner, Université Lyon 1 / Hospices Civils de Lyon

lea.payen@univ-lyon1.fr

PRODHOMME Mélanie
PUISIEUX Alain

Head of the team

Professor and Hospital Practitioner, Université Lyon 1 / Centre Léon Bérard
alain.puisieux@lyon.unicancer.fr

RUBY Samia

Senior researcher (CRCN), Inserm

samia.ruby@lyon.unicancer.fr

SANLAVILLE Amélien

Senior researcher, Centre Léon Bérard

amelien.sanlaville@lyon.unicancer.fr

TISSIER Agnès

Senior researcher (CRCN), Inserm

agnes.tissier@lyon.unicancer.fr

VIGNERON Arnaud

Lecturer, Université Lyon 1

arnaud.vigneron@lyon.unicancer.fr

WIERINCKX Anne
Lecturer, Université Lyon 1

anne.wierinckx@univ-lyon1.fr

Voir les objectifs et projets Voir les publications

Collaborations
- Frederic Hollande, Victorian Comprehensive Cancer Centre, University of Melbourne, Australia. Creation of an International Associated Laboratory (LIA, INSERM/CNRS) in 2017.

- Emmanuelle Charafe-Jauffret and Christophe Ginestier, Cancer Research Centre of Marseille, France.

- Eugene Tulchinsky, Leicester Cancer Research Centre, UK.

- Thomas Brabletz, University Erlangen, Germany.

- Christoph Klein, University of Regensburg, Germany.

- Jean-Sébastien Hoffmann, Cancer Research Centre of Toulouse, France.

Grants

- Institut National du Cancer
- Ligue nationale contre le Cancer, équipe labellisée
- Fondation ARC
- Fondation pour la Recherche Médicale
- Joint transnational call TRANSCAN

OBJECTIVES

The plasticity of cancer cells underlies their capacity to adapt to the numerous selective pressures they encounter from tumor initiation to metastatic spread. At the crux of this concept is the epithelial-mesenchymal transition (EMT). EMT is a latent embryonic transdifferentiation program that turns polarized epithelial cells into motile mesenchymal ones. In human cancers of epithelial origin, EMT commitment has primarily been implicated in cancer cell invasion and metastatic spread. Our observations further highlight the role of EMT-inducing transcription factors (EMT-TFs) of the TWIST and ZEB families in the initiation and the development of primary tumors, including neuroblastomas, breast cancers and melanomas. Consistent with this notion, we have shown that EMT commitment endows cancer cells with stemness properties and that EMT-TFs inhibit the p53- and Rb-dependent oncosuppressive pathways and cooperate with mitogenic oncoproteins to foster malignant transformation in vitro and in vivo. Their oncogenic functions are dependent on their modulatory role on cell differentiation, EMT-TFs displaying either oncosuppressive or oncogenic activities in neural-crest cell-derived melanocytes according to their impact on MITF-driven differentiation programs. Of utmost importance, EMT has been shown in vitro and in vivo to confer tumour aggressiveness and resistance to both conventional and targeted therapies. Targeting EMT-driven tumour cell plasticity may therefore represent an innovative approach for cancer therapy.

PROJECT

Recently, we have demonstrated that EMT-TFs are expressed in normal mammary stem cells and that their expression influences the entire natural history of breast tumourigenesis. Indeed, unlike differentiated cells, human mammary stem cells have the innate capacity to withstand an aberrant mitogenic activation. This property is based on an antioxidant program driven by ZEB1, a potent EMT-TF, and by the methionine sulfoxide reductase MSRB3, a ZEB1 transcriptional target. This pre-emptive program prevents the formation of oncogene-induced DNA damage, a major cause of genomic instability, and influences the emergence of cancer-associated events. Overall, these data suggest that malignant transformation of mammary stem cells does not hinge on genomic instability and indicate that intrinsic properties of the cell-of-origin dictate the genomic landscape of breast cancers. The aims of our team are: i) to characterize the oncogenic functions of EMT-TFs, ii) to decipher their respective roles in the early stages of tumorigenesis and their influence on the clonal dynamics of tumorigenesis, and iii) to determine the impact of their expression on resistance to anti-cancer therapies, including conventional chemotherapies, targeted therapies and immune therapies, with breast cancers and melanomas as priority tumor types. The ultimate objective is to design approaches promoting the blockade EMT-driven plasticity, with the goal to increase cancer cell sensitivity to anti-cancer therapeutics.


Subpopulations of normal mammary epithelial cells exhibit distinct early responses to an oncogenic event.
While differentiated cells undergo massive DNA damage, mammary stem cells can withstand aberrant mitogenic signaling through a pre-emptive program driven by ZEB1 and MSRB3. This specific behavior impacts the natural history of breast tumorigenesis by favoring malignant transformation in the absence of genomic instability (figure from Morel et al., Nat Med 2017).

MAIN PUBLICATIONS

Puisieux A, Pommier RM, Morel AP, Lavial F. Cellular pliancy and the multistep process of tumorigenesis. Cancer Cell, 33: 164-172, 2018.

Caramel J, Ligier M, Puisieux A. Pleiotropic Roles for ZEB1 in Cancer. Cancer Research, 78: 30-35, 2018.

Morel AP, Ginestier C, Pommier RM, Cabaud O, Ruiz E, Wicinski J, Devouassoux-Shisheboran M, Combaret V, Finetti P, Chassot C, Pinatel P, Fauvet F, Saintigny P, Thomas E, Moyret-Lalle C, Lachuer J, Despras E, Jauffret JL, Bertucci F, Guitton J, Wierinckx A, Wang Q, Radosevic-Robin N, Penault-Llorca F, Cox DG, Hollande F, Ansieau S, Caramel J, Birnbaum D, Vigneron AM, Tissier A, Charafe-Jauffret E, Puisieux A. A stemness-related ZEB1-MSRB3 axis governs cellular pliancy and breast cancer genome stability. Nature Medicine, 23: 568-578, 2017.

Richard G, Dalle S, Monet MA, Ligier M, Boespflug A, Pommier RM, de la Fouchardière A, Perier-Muzet M, Depaepe L, Barnault R, Tondeur G, Ansieau S, Thomas E, Bertolotto C, Ballotti R, Mourah S, Battistella M, Lebbé C, Thomas L, Puisieux A*, Caramel J*. *corresponding authors. ZEB1-mediated melanoma cell plasticity enhances resistance to MAPK inhibitors. EMBO Molecular Medicine, 8: 1143-1161, 2016.

Puisieux A, Brabletz T, Caramel J. Oncogenic roles of EMT-inducing transcription factors. Nature Cell Biology, 16: 488-494, 2014. Highly cited paper, top 1% of the academic field of Molecular Biology & Genetics.

Caramel J, Papadogeorgakis E, Hill L, Browne GJ, Richard G, Wierinckx A, Saldanha G, Hutchinson P, Tse G, Lachuer J, Puisieux A, Pringle JH, Ansieau S, Tulchinsky E. A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell, 24: 466-480, 2013.

Marcel V, Ghayad SE, Belin S, Therizols G, Morel AP, Solano-Gonzalez E, Vendrell JA, Hacot S, Mertani HC, Albaret MA, Bourdon JC, Jordan L, Thompson A, Tafer Y, Cong R, Bouvet P, Saurin JC, Catez F, Prats AC, Puisieux A, Diaz JJ. P53 acts as a safeguard of translational control by regulating fibrillarin and rRNA methylation in cancer. Cancer Cell, 24: 318-330, 2013.

Morel A-P, Hinkal GW, Thomas C, Fauvet F, Courtois-Cox S, Wierinckx A, Devouassoux-Shisheboran M, Treilleux I, Tissier A, Gras B, Pourchet J, Puisieux I, Browne G, Spicer DB, Lachuer J, Ansieau S, Puisieux A. EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors in transgenic mice. PLoS Genetics, 8: e1002723, 2012.

Ansieau S, Bastid J, Doreau A, Morel AP, Bouchet BP, Thomas C, Fauvet F, Puisieux I, Doglioni C, Piccinin S, Maestro R, Voeltzel T, Selmi A, Valsesia-Wittmann S, Caron de Fromentel C, Puisieux A. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell, 14: 79-89, 2008.

Morel A-P, Lièvre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. Generation of breast cancer-stem cells through epithelial-mesenchymal transition. PLoS One, 3: e288, 2008. Highly cited paper, top 1% of the academic field of Clinical Medicine.

Mehlen P, Puisieux A. Metastasis: a question of life or death. Nature Reviews Cancer, 6: 449-458, 2006.

Valsesia-Wittmann S, Magdeleine M, Dupasquier S, Garin E, Jallas AC, Combaret V, Krause A, Leissner P, Puisieux A. Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells. Cancer Cell, 6: 625-630, 2004.

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