CONTACT

Co-direction

Julie Caramel, CRCN Inserm
julie.caramel@lyon.unicancer.fr

Stéphane Dalle, PU-PH
stephane.dalle@chu-lyon.fr

Cheney D, 2ème étage
Centre Léon Bérard

THOMAS Luc
Enseignant Chercheur (PU-PH)
luc.thomas@chu-lyon.fr
MASSE Ingrid

Enseignant Chercheur (MCU)
ingrid.masse@lyon.unicancer.fr

LOPEZ Jonathan

Enseignant chercheur (MCU PH)
jonathan.lopez@chu-lyon.fr

DE LA FOUCHARDIERE Arnaud
BOESPFLUG Amélie
DURAND Simon

Chercheur post-doctorant
simon.durand@lyon.unicancer.fr

HOULIER Aurélie
LIGIER Maud
LOPEZ-RAMIREZ Noémie
RUNEL Gaël
TANG Yaqi
GRIMONT Maxime
VASSEUR Damien

Master 2 student

Voir les objectifs et projets Voir les publications

Main collaborations :
National :
Christophe Caux, CRCL
Zdenko Herceg, IARC
Robert Ballotti, Corine Bertolotto, Nice
Céleste Lebbé, Samia Mourah, Hôpital Saint Louis
Laurence Zitvogel, IGR
Lionel Larue, Orsay
Muriel Cario André, Bordeaux
Nathalie Andrieu, Toulouse
Irwin Davidson, Strasbourg
Jean-Nicolas Volff, IGFL 

International :
Martin McMahon, Salt Lake City
Manfred Schartl, Würzbürg
Susana Puig, Barcelona

Start-up :
Oncofactory, Lyon
Bioméca, Lyon

Main financial supports :
Institut National du Cancer
Ligue contre le Cancer, Comité de l’Ain
Fondation ARC
Fondation pour la Recherche Médicale
Fondation de France
Société Française de Dermatologie
Association « Melarnaud »

The ”Cancer Cell Plasticity in Melanoma” is an emerging team co-headed by Julie Caramel, CRCN INSERM, and Stéphane Dalle, PU-PH, head of the oncodermatology unit at Lyon South Hospital (since 2017). They have structured since 2013, a research group, focused on melanoma, gathering basic researchers and clinicians with complementary expertise on this cutaneous pathology in Lyon. This group has been initially set up within the team of Alain Puisieux specialized in “EMT and cancer cell plasticity”.

OBJECTIVES

Cutaneous melanoma is the most aggressive type of skin cancer, characterized by an exacerbated cancer cell plasticity that is supposed to contribute to intra-tumor heterogeneity and resistance to treatment. Despite recent progress provided by targeted and immunotherapy, a significant number of metastatic melanoma patients still present innate or acquired resistance. Increasing evidence suggest that in addition to genetic alterations, resistance development may be attributed to phenotypic adaptations through transcriptional and epigenetic processes. A complete understanding of the reprogramming mechanisms underlying phenotypic adaptations of melanoma cells, their complex interplay with the microenvironment and thus, their exceptional capacity to develop resistance to current therapeutic strategies, is still required in order to define novel targets and design new combination therapies. 

PROJECTS

Melanoma intra-tumor heterogeneity relys on a “phenotype-switching” model wherein melanoma cells shift between a proliferative/differentiated and an invasive/stem-like state. MIcrophthalmia-associated Transcription Factor (MITF), the master regulator of melanocyte differentiation, is a major marker of the proliferative phenotype, whose loss in melanoma cells is sufficient to induce a reprogramming towards an invasive and stem-like phenotype. In this context, our previous work demonstrated that transcription factors known for their role in EMT (epithelial-to-mesenchymal transition) in carcinomas, also play major functions in melanoma. EMT is a major cancer cell plasticity process, orchestrated by a network of transcription factors (EMT-TFs), including members of the ZEB, SNAIL and TWIST families, that interact with epigenetic regulators (Caramel et al., Cancer Res. 2018; Puisieux et al., Nat. Cell Biol. 2014). We demonstrated that EMT-TF reprogramming regulates melanomagenesis, cancer cell plasticity and adaptive resistance to targeted therapies (Caramel et al., 2013; Richard et al., 2016). Namely, ZEB1 is a major regulator of MITF-mediated phenotype switching towards a Neural Crest Stem Cell-like phenotype. Preliminary data also suggest that ZEB1 directly regulates Tetraspanin 8 (Tspan8), a transmembrane protein that we previously showed as a major inducer of the invasive phenotype (Agaësse et al., 2017a, 2017b, El Kharbili et al., 2017, 2019)

While the role of cancer cell phenotype plasticity in favoring the emergence of resistance to targeted therapies has been deeply investigated in melanoma, the consequences on immune escape and immunotherapy response remain poorly characterized. Our projects aim at further characterizing the mechanisms underlying the adaptation of melanoma tumors, viewed as complex ecosystems, and the acquisition of resistance to targeted therapies and immunotherapies. Based on our strong expertise in melanoma and cancer cell plasticity and thanks to a strong collaborative network (epigenetics, immunology, biomechanics), we will use innovative methods in vitro and in vivo (in mouse, fish and avian embryo models), as well as in cohorts of human samples, to:

(i) further investigate the molecular mechanisms sustaining the plasticity of cancer cells, including the identification of transcriptional networks and epigenetic regulators;

(ii) analyze biomechanical forces in vivo during the transition to the invasive state;

(iii) decipher the crosstalk of tumor cells with their immune microenvironment, the mechanisms of immune evasion and resistance, including a detailed characterization of intra-tumor heterogeneity in patients samples;

(iv) develop original strategies for targeting cancer cell plasticity in order to overcome melanoma resistance to current therapeutic strategies, which will in turn provide a strong rationale to the development of new combination therapies in the treatment of malignant melanoma.


PUBLICATIONS

2019
-  Long GV, …, Dalle S, …, Mitchell TC. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019 Jun 17.

-  Péron J, Lambert A, Munier S, Ozenne B, Giai J, Roy P, Dalle S, Machingura A, Maucort-Boulch D, Buyse M. Assessing long-term survival benefits of immune checkpoint inhibitors using the net survival benefit. J Natl Cancer Inst. 2019 Mar 5.

-  El Kharbili M, Agaësse G, Barbollat-Boutrand L, Pommier RM, de la Fouchardière A, Larue L, Caramel J, Puisieux A, Berthier-Vergnes O and Masse I. Tspan8-β-catenin positive feedback loop promotes melanoma invasion. Oncogene, 2019 Jan 24.

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

-  Eggermont AMM, …, Dalle S, …, Robert C. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. The New England Journal of Medicine, 378:1789-1801, 2018.

2017

-  Morel AP, Ginestier C, Pommier RM, Cabaud O, Ruiz E, Wicinski J, Devouassoux-Shisheboran M, Combaret V, Finetti P, Chassot C, Pinatel C, 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.

-  Jacquelot N, Roberti MP, Enot DP, Rusakiewicz S, Ternès N, Jegou S, Woods DM, Sodré AL, Hansen M, Meirow Y, Sade-Feldman M, Burra A, Kwek SS, Flament C, Messaoudene M, Duong CPM, Chen L, Kwon BS, Anderson AC, Kuchroo VK, Weide B, Aubin F, Borg C, Dalle S, Beatrix O, Ayyoub M, Balme B, Tomasic G, Di Giacomo AM, Maio M, Schadendorf D, Melero I, Dréno B, Khammari A, Dummer R, Levesque M, Koguchi Y, Fong L, Lotem M, Baniyash M, Schmidt H, Svane IM, Kroemer G, Marabelle A, Michiels S, Cavalcanti A, Smyth MJ, Weber JS, Eggermont AM, Zitvogel L. Predictors of responses to immune checkpoint blockade in advanced melanoma. Nature Communications, 8:592, 2017.

-  Yeh I, Lang UE, Durieux E, Tee MK, Jorapur A, Shain AH, Haddad V, Pissaloux D, Chen X, Cerroni L, Judson RL, LeBoit PE, McCalmont TH, Bastian BC and de la Fouchardière A. Combined activation of MAP kinase pathway and β-catenin signaling cause deep penetrating nevi. Nature Communications, 8:644, 2017.

-  Agaësse G, Barbollat-Boutrand L, Sulpice E, Bhajun R, El Kharbili M, Berthier-Vergnes O, Degoul F, de la Fouchardière A, Berger E, Voeltzel T, Lamartine J, Gidrol X and Masse I. A large-scale RNAi screen identifies LCMR1 as a critical regulator of Tspan8-mediated melanoma invasion. Oncogene, 36:446–457, 2017.

-  Weber J, …, Dalle S, …, Ascierto PA; CheckMate 238 Collaborators. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. The New England Journal of Medicine, 377:1824-1835, 2017.

2016
-  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. ZEB1-mediated melanoma cell plasticity enhances resistance to MAPK inhibitors. EMBO Molecular Medicine, 8: 1143-1161, 2016.

-  Jacquelot N, Enot DP, Flament C, Vimond N, Blattner C, Pitt JM, Yamazaki T, Roberti MP, Daillère R, Vétizou M, Poirier-Colame V, Semeraro M, Caignard A, Slingluff CL Jr, Sallusto F, Rusakiewicz S, Weide B, Marabelle A, Kohrt H, Dalle S, Cavalcanti A, Kroemer G, Di Giacomo AM, Maio M, Wong P, Yuan J, Wolchok J, Umansky V, Eggermont A, Zitvogel L. Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma. The Journal of Clinical Investigation, 126:921-37, 2016.

-  Perier-Muzet M, Boespflug A, Poulalhon N, Caramel J, Breton AL, Thomas L, Dalle S. Dermoscopic Evaluation of Melanocytic Nevi Changes With Combined Mitogen-Activated Protein Kinase Pathway Inhibitors Therapy for Melanoma. JAMA Dermatology, 152:1162-1164, 2016.

2014
-  Puisieux A, Brabletz T, Caramel J. Oncogenic roles of EMT-inducing transcription factors. Nature Cell Biology, 16: 488-494, 2014. 


2013
-  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. Best of Cancer Cell 2013.

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