Presentation
Equipe de Recherche Fondamentale 6 " Genetique et Physiopathologie des Cancers épithéliaux "
Dr Thierry MAGNALDO, DR2 CNRS / Guerrino MENEGUZZI, DR1 INSERM, Chefs d'Equipe
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Présentation Parmi les cancers épithéliaux associés au vieillissement, les carcinomes épidermoïdes sont de loins les plus fréquents (figure1) et sont généralement létaux. Les propriétés invasives des cancers épithéliaux dépendent d'interactions entre le tissu tumoral et son micro-environnement. La nature exacte de ces interactions reste à préciser. La pathogénèse des carcinomes cutanés humains est sujette à des facteurs génétiques, environnementaux et liés à l’âge. Afin d’étudier les évènements moléculaires associés à la cancerogenèse épithéliale, nous avons mis au point des systèmes expérimentaux de susceptibilité aux cancer de la peau. Ces modèles expérimentaux reposent sur l’étude de cellules de patients souffrant de syndromes génétiques rares, fortement prédisposés, soit au cancer cutané non métastatiques (syndrome de Gorlin dû à l’altération de la voie Sonic Hedghog) soit préférentiellement aux cancers cutanés fortement métastatiques (xeroderma pigmentosum, une maladie de la réparation de l’ADN par excision de nucléotides). Le développement de cultures de peaux organotypiques indique que les interactions épithélium-stroma sont affectées de façon spécifique dans chacune de ces pathologies et que les fibroblastes du stroma pourraient jouer un rôle clé dans l’agressivité tumorale. Ainsi, la compréhension des interactions moléculaires entre la cellule tumorale et son environnement devrait permettre le développement de stratégies antitumorales ciblées et innovantes. |
adaptée de DePihno, R., Nature, 408, (2000)The age of Cancer.
Pathologic organotypic skin cultures (OSC), developed from cells isolated from patients suffering either from the cancer-susceptibility genetic diseases xeroderma pigmentousm, a, or Gorlin’ syndrome, b. |
Projet de Recherche
Projet de Recherche
Les cancer épithéliaux
- Le développement des cancers épithéliaux et leur propriétés invasives sont étroitements dépendants des intéractions entre la cellule tumorale et son microenvironnement mais la nature exacte de ces interactions reste à documenter.
- Chez l’homme, la peau est l’organe le plus touché par le carcinome. Comme pour tous les carcinomes, l’âge est un facteur de risque majeur. La peau constitue donc un modèle prototype pour l’étude des interactions épithélio-mesenchymateuse au cours du vieillissement et de la cancérogenèse.
- L’étude de cellules de patients atteints de syndromes génétiques susceptibles aux carcinomes cutanés (xeroderma pigmentosum, une maladie de la réparation de l’ADN ; syndrome de Gorlin : défaut de signalisation Sonic Hedgehog dû à la mutation du récepteur PATCHED) suggère que les deux compartiments, epithélial et mésenchymateux, sont affectés en absence de stress génotoxique ou de stimuli extérieur.
- Dans les cultures organotypiques, les kératinocytes primaires des patients présentent des caractères d’invasivité et de différenciation de type tumoral, et qui sont agravées en présence des fibroblastes autologues. Les fibroblastes de patients surexpriments notamment de facteurs associés aux remaniements de la matrice extracellulaire (MMP1, MMP3), à la prolifération kératinocytaire (KGF/FGF-7), ou à l’inflammation (CXCL12/SDF1a).
- Ces fibroblastes présentent spontannément et, de façon autonome, des caractéristiques de cellules stromales associées aux tumeurs épithéliales (carcinoma associated fibroblasts, CAF). Ils pourraient jouer un rôle prépondérant dans les étapes précoces du développement tumoral et déterminer l’agressivité des tumeurs. L’identification et la compréhension des voies moléculaires impliquées dans le développement des tumeurs épithéliales dans leur contexte stromal permettront de mieux cibler les traitements antitumoraux.
Equipe de Recherche
Equipe de Recherche
Tel : + 33 (0)4 93 37 76 70, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
MENEGUZZI Guerrino, DR1 Inserm, Chef d'Equipe - Co-direction
Tel : + 33 (0)4 93 37 77 79, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
AL-GARAGHULI Sahar, Thèse, CNOUSTel : + 33 (0)4 93 37 77 47, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
GACHE Yannick, CR1 InsermTel : + 33 (0)4 93 37 77 47, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
ROUANET Sophie, ThèseTel : + 33 (0)4 93 37 76 70, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
Chercheurs Cliniciens
LACOUR Jean-Philippe, PU-PH CHU NiceTel : + 33 (0)4 92 03 64 89, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
PERRIN Chistophe, PH, CHU NiceTel : + 33 (0)4 93 37 XX XX, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
Brevets
Brevets
2003 : Thierry Magnaldo, A. Sarasin :« Use of the CD24 marker gene for the selection of keratinocyte stem cells transformed by exogenous sequences »International patent nbr WO 03004655, 2003.
Publications
Publications
Valin, A., Barnay-Verdier, S., Robert, T., Ripoche, H., Brellier, F., Chevallier-Lagente, O., Avril, M. F. and Magnaldo, T. (2008). PTCH +/- dermal fibroblasts isolated from healthy skin biopsy of Gorlin syndrome patients exhibit features of carcinoma associated fibroblasts. Plos One. 4(3):e4818.
Gendronneau, G., Sukhvinder S. Sidhu, S., Delacour, D., Dang, T., Calonne C., Houzelstein, D., Magnaldo, T., and Poirier, F. Galectin-7 in the control of epidermal homeostasis after injury. Mol. Biol. Cell, 2008 Oct 1.
Brellier, F., Bergoglio, V., Valin, A., Barnay, S., Chevallier-Lagente, O., Viel, P., Spatz, A., Gorry, P., Avril, M. and Magnaldo, T. (2008). Heterozygous mutations in the tumor suppressor gene PATCHED provoke basal cell carcinoma-like features in human organotypic skin cultures Oncogene, (04 Aug 2008), doi: 10.1038/onc.2008.260.
Frechet, M., Warrick, E., Vioux, C., Benhamou, S., Spatz, A., Sarasin, A., Bernerd, F. and Magnaldo, T. (2008) Over expression of matrix metallo-proteinase 1 in dermal fibroblasts from DNA repair deficient / cancer prone xeroderma pigmentosum group C patients, Oncogene, 27, 5223 - 5232.
Brellier, F., Valin, A., Chevallier-Lagente, O., Gorry, P., Avril, M-F., and Magnaldo, T. Ultraviolet responses of Gorlin syndrome primary skin cells. British J. Dermatol. 2008, 59, 445-452.
Bergoglio, V., Emilie Warrick, E., Chevallier-Lagente, O., and Magnaldo, T. (2008) Cutaneous gene therapy : the graft takes / Thérapie génique cutanée : la greffe prend / Médecine/Science, 24, 607-14.
Bergoglio, V., Larcher, F., Chevallier-Lagente, O., Bernheim, A., Danos, O., Sarasin, A, Del Rio, M.D., and Magnaldo, T. 2008 Safe Selection of Genetically Manipulated Human Primary Keratinocytes with Very High Growth Potential Using CD24. Mol. Therapy. 12, 2186-2193.
Groisman, R., Kuraoka, I.,Chevallier, O., Gaye, N., Magnaldo,T., Tanaka, K.,5, Harel-Bellan, A., Kisselev, AF., and Yoshihiro Nakatani (2006) CSA-dependent degradation of CSB by the ubiquitin-proteasome pathway establishes a link between complementation factors of the Cockayne syndrome. Genes and Dev., 20 , 1429-1434.
Brellier, F., Marionnet, C., Chevallier-Lagente, O., Toftgard, R., Mauviel, A., Sarasin, A. and Magnaldo, T. (2004). Ultraviolet radiation represses PATCHED transcription in human epidermal keratinocytes through an AP1-depedent process. Cancer Res 64, 2699-2704.
Magnaldo, T. (2004). Xeroderma pigmentosum: from genetics to hopes and realities of cutaneous gene therapy. Expert Opin Biol Ther 4, 169-179.
Gache Y, Baldeschi C, Del Rio M, Gagnoux-Palacios L, Larcher F, Lacour JP, Meneguzzi G. (2004) "Construction of skin equivalents for gene therapy of recessive dystrophic epidermolysis bullosa". Hum Gen Ther. Oct;15(10):921-33.
Gache Y., Charlesworth A., Philipe N., Vabres P., Meneguzzi G. (2004) "Identification de formes transitoires d’épidermolyses bulleuses avec atrésie pylorique". J . Invest. Dermatol. 123 :P25
Capt A., Spirito F., Guaguere E., Spadafora A., Ortonne J-P. and Meneguzzi G. (2005) "Inherited junctional epidermolysis bullosa in the German pointer: establishment of a large animal model for the condition". J Invest Dermatol 124:530-5.
Gagnoux-Palacios L., Hervouet C., Spirito F., Roques S., Mezzina M., Danos O., Meneguzzi G. (2005) "Assessment of optimal transduction of primary human skin keratinocytes by viral vectors". J Gene Med. J Gene Med. 7: 1178-1186.
Baudoin C., Fantin L. and Meneguzzi G. (2005) "Proteolytic processing of the laminin 3 G domain mediates assembly of hemidesmosomes but has no role on keratinocyte migration. J Invest Dermatol. 125(5):883-8.
Fitsialos, AA. Chassot, L. Turchi, M.A. Dayem, K. LeBrigand, C. Moreilhon, G. Meneguzzi, R. Busca, B. Mari, P. Barbry and G. Ponzio. (2007) Transcriptional signature of epidermal keratinocytes subjected to in vitro SCRATCH wounding, reveals selective roles for ERK1/2, p38 and PI3K signalling pathways J. Biol. Chem 282, p15090-102.
A.A. Chassot, L. Turchi, T. Virolle, G. Fitsialos, M. Batoz, M. Deckert, V. Dulic, G. Meneguzzi, R. Busca and G. Ponzio. (2007) Id3 is a novel regulator of p27kip1 mRNA in early G1 phase and is required for cell cycle progression. Oncogene 26, p5772-83.
M D Alessio, G Zambruno, A Charlesworth, J-P Lacour, G. Meneguzzi (2008) "Immunofluorescence analysis of villous trophoblasts: a new tool for early prenatal diagnosis of inherited epidermolysis bullosa with pyloric atresia". J Invest Dermatol.128(12):2815-9.
G Fitsialos, I Bourget, S Augier, A Ginouves, R Rezzonico, T Odorisio, F Cianfarani, T Virolle, J Pouyssegur, G. Meneguzzi, E Berra, G Ponzio, R Busca. (2008) HIF1 transcription factor regulates laminin-332 expression and keratinocytes migration . J Cell Sci. 15;121 (Pt 18):2992-3001.
Baby Team Cédric Gaggioli
Baby Team Cédric Gaggioli " Tumor-Stroma Crosstalk in Invasive Cancer "
Presentation
In primary tumors, cancer cells are immersed in a complex microenvironment network comprising numerous cells, including carcinoma associated fibroblasts (CAF). Tumor-stroma crosstalk plays a major role in carcinoma development and invasion. We have previously demonstrated the crucial role of Janus Kinase dependent signaling pathway, in CAF cells, for matrix remodeling and tracks formation for cancer cells to invade. However, how “normal” resident fibroblasts are converted into pro-invasive CAF cells remains an open question. Malignant cells themselves promotes carcinogenesis through cytokines and growth factors secretion that influence stroma cells behaviour, which in return influence carcinoma cells invasion and malignancy. In line with our previous research, we aim at uncovered signaling pathways and molecules that govern stromal fibroblasts and carcinoma cells crosstalk during invasion, which could lead to the identification of therapeutic target for aggressive and metastatic cancer.
Projet de Recherche
The project presents two major axes focused on :
Investigation of the signaling pathways that in SCC cells mediates the pro-invasive conversion of resident fibroblasts
We aim at identifying pathway in pro-invasive CAFs conversion from primary human dermal fibroblasts (HPF) isolated from children foreskin. Using in vitro matrix remodeling and three-dimensional organotypic invasion assay.
Uncovering the signaling molecules secreted by pro-invasive “activated” fibroblasts that leads to SCC cells invasion
We aim at identifying matrix proteins differentially assemble within the matrix by stimulated HDF cells compare to their non-stimulated counterpart. A comparative proteomic approach will be used to qualitatively and quantitatively identify matrix proteins assembled within the matrix of stimulated HDF cells compared to the non-stimulated counterpart. Matrix molecules layered down by activated HDF cells to culture Petri dishes will be analyzed and identified using a mass spectrometry approach. The possible role that matrix components, selected on the basis of data published in the literature, may have on SCC cell behaviour will then be assessed by conventional cell biology procedures, which include cell adhesion, migration and invasion in three dimensional organotypic assays. This approach is expected to lead to the identification of secreted molecules involved in SCC cell invasion induced by CAF.
The proposed research projects aim at address fundamental aspects on invasive carcinoma development with a particular attention on the stroma as therapeutic target. Besides this contribution this project aims at identifying potential clinical target in a long-term goal for developing new strategies to counteract cancer cell invasion and metastasis.
Equipe de Recherche
Tel : + 33 (0)4 93 37 77 53, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
ALBRENGUES Jean, ThèseTel : + 33 (0)4 93 37 77 53, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
BOURGET Isabelle, IE1 InsermTel : + 33 (0)4 93 37 77 53, Mail : This e-mail address is being protected from spambots. You need JavaScript enabled to view it
Publications
Sanz-Moreno V†, Gaggioli C†, Yeo M, Albrengues J, Wallberg F, Viros A, Hooper S, Mitter R, Féral CC, Cook M, Larkin J, Marais R, Meneguzzi G, Sahai E, Marshall CJ. ROCK and JAK1 Signaling Cooperate to Control Actomyosin Contractility in Tumor Cells and Stroma. Cancer Cell. 2011 Aug 16;20(2):229-45. †Contributed equally to this work.
Hooper S, Gaggioli C, Sahai E. A chemical biology screen reveals a role for Rab21-mediated control of actomyosin contractility in fibroblast-driven cancer invasion. Br J Cancer. 2010 Jan 19;102(2):392-402.
Medjkane, S., Perez-Sanchez, C., Gaggioli, C, Sahai, E., and Treisman, R. Myocardin-Related Transcription Factors and SRF are required for cytoskeletal dynamics, invasion and experimental metastasis. Nature Cell Biology. 2009 Mar;11(3):257-68.
Gaggioli C. Collective invasion of carcinoma cells: when the fibroblasts take the lead. Cell Adh Migr. 2008 Jan-Mar;2(1)
:45-7.
Gaggioli C., Hooper H., Hidalgo-Carcedo C., Grosse R., Marshall JF., Harrington K., and Sahai E. Fibroblast led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nature Cell Biology, 2007 Dec;9(12):1392-400.
Gaggioli C. and Sahai E. Melanoma Invasion: Current knowledge and future directions. Pigment Cell Res. 2007 Jun;20
(3):161-72. Review.
Gaggioli C., Robert G., Bertolotto C., Bailet O., Abbe P., Spadafora A, Bahadoran P, Ortonne J-P, Baron V, Ballotti R. & Tartare-Deckert, S. Tumor-Derived Fibronectin Is Involved in Melanoma Cell Invasion and Regulated by V600E B-Raf Signaling Pathway. J Invest Dermatol. 2007 Feb;127(2):400-10.
Guillaume Robert, Cédric Gaggioli, Carine Chavey, Olivier Bailet, Patricia Abbe, Edith Aberdam, Sabatie Emillie, Amparo Cano, Garcia De Herreros, Robert Ballotti and Sophie Tartare-Deckert. SPARC represses E-cadherin expression and induces mesenchymal transition during melanoma development. Cancer Research 2006 Aug 1;66(15):7516-23.
Roser Buscà, Edurne Berra, Cédric Gaggioli, Barbara Marchetti, Raphaël Thyss, Giorgos Fitsialos, Mehdi Khaled, Lionel Larribère, Corine Bertolotto, Thierry Virolle, Pascal Barbry, Jacques Pouysségur, Gilles Ponzio and Robert Ballotti. Hypoxia Inducible Factor 1 alpha is a new target of Microphthalmia Associated Transcription Factor (MITF) in melanoma cells. J Cell Biol. 2005 Jul 4;170(1):49-59.
Gaggioli C. Deckert M., Robert G., Abbe P., Batoz M., Ehrengruber M.U., Ortonne J-P, Ballotti R. & Tartare-Deckert, S. HGF induces. fibronectin matrix synthesis in melanoma cells through MAP kinase-dependent signaling pathway and induction of Egr-1. Oncogene 2005 Feb 17;24(8):1423-33.
Marella M, Gaggioli C., Batoz M., Deckert M., Tartare-Deckert S. & Chabry J. Pathological prion protein exposure switches on neuronal MAP-kinase pathway resulting in microglia recruitment. J Biol Chem. 2005 Jan 14;280(2):1529-34.
Cédric Gaggioli, Roser Buscà, Patricia Abbe, Jean-Paul Ortonne, and Robert Ballotti. Expression of Microphthalmia-associated Transcription Factor (MITF) is Required but does not Induce Melanogenesis in mammalian melanocytic cells. Pigment Cell Res. 2003 Aug;16(4):374-82.