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Team Thierry MAGNALDO

Presentation


Basic Research Team « Genetics and Physiopathology of Eptihelial Cancers »


Dr Thierry MAGNALDO, DR2 CNRS, Team Leader     




Summary

 

Among the epithelial cancers that arise with ageing, squamous cell carcinomas are by far the most common (figure 1) and are generally lethal.

Invasiveness of epithelial cancers is known to depend on the interactions between the tumor cells and their microenvironment..

However, the exact nature of such interactions deserves further investigations. Pathogenesis of human skin carcinomas is subject to genetic, environmental, and age-related parameters.

Our experimental settings aim at documenting molecular events associated with epithelial carcinogenesis and thus contribute to innovative therapeutic approaches.


We set up experimental models of susceptibility to skin cancer based on rare genetic conditions such as the Gorlin’ or the Xerodema pigmentosum (XP) syndromes that are due to distinct molecular alterations (Nucleotide Excision Repair and Sonic Hedgehog signaling pathway, respectively).

Most notably, Gorlin’syndrome is associated with non metastatic skin carcinoma while rates of metastatic cancers are very elevated in XP patients.

Development of pathological organotypic skin cultures in vitro indicate thatstroma-epithelium interactions are affected in a disease specific manner and suggests that patients’ fibroblasts may play a key role in early tumor development and determine aggressiveness (figure 2).

Our models will contribute to deciphering molecular clues underlying stroma-cancer evolution and improve targetting of antitumoral treatments.



Figure 1 Figure 1

Figure 1

adapted from de DePihno, R., Nature, 408, (2000)The age of Cancer.
Please note that about 30 % human cancers are basal and squamous cell carcinomas

Figure 2 Figure 2
Figure 2

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.
In situ labellings are as indicated (Ki67, left; Cyclin D1 right) and show high rates of cell multiplication in epithelial invasions within the stroma.

Research Project


Research Project


Epithelial cancers


- Epithelial cancers and their invasive capacity are known to depend on interaction between the tumor cell and it microenvironment but the exact nature of these interactions deserves further investigations.

- In the human, skin is the organ most often victim of carcinoma. As for all carcinoma, age is a major risk factor. Skin thus constitutes a prototype model for studying epithelio-mesenchymal interactions upon aging and carcinogenesis.

- Study of cells isolated from patients with the rare cancer prone genetic diseases, Xerodema pigmentosum (defect of nucleotide excision repair) or Gorlin’syndrome (defect of Hedgehog signaling due to PATCHED mutation) indicated that both epithelial and mesenchymal cells were affected in absence of genotoxic stress or external stimuli.

- Notably, in organotypic skin cultures, primary patients keratinocytes exhibited tumor-like features of differenciation and invasiveness that were further enhanced in the presence of autologous fibroblasts. Patient fibroblasts overexpressed factors associated to extracellular matrix modifications (MMP1, MMP3), cell proliferation (KGF/FGF7), or inflammation (SDF1a/CXCL12).

- Patients fibroblasts thus spontaneously present characteristics of stromal cells called carcinoma associated fibroblasts (CAF). Patients fibroblasts could thus play a key role in early tumor development and determine agressiveness. Deciphering molecular pathways involved in epithelial cancer development within its stromal context will contribute to better targetting antitumoral treatments.

Research Team


Research Team



MAGNALDO Thierry, DR2 CNR, Team Leader
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AL-QARAGHULI Sahar, Thèse, CNOUS
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GACHE Yannick, CR1 Inserm
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GONCALVES Maria, Thèse

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MULLER Margot, Thèse

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ROUANET Sophie, Thèse

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L'YVONNET Thibaud, Master 1 INSERM

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Chercheurs Cliniciens


PERRIN Chistophe, PH, CHU Nice
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(Fev 2016)


Patents

Patents


2009 : A.Valin, Thierry Magnaldo :
« Method for determining a predisposition to basal cell carcinoma and for screening treatments thereof »
International patent nbr WO 2010/01561, 2009.

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


2015


Gache Y, Brellier F, Rouanet S, Al-Qaraghuli S, Goncalves-Maia M, Burty-Valin E, Barnay S, Scarzello S,

Ruat M, Sevenet N, Avril MF, Magnaldo T.

Basal Cell Carcinoma in Gorlin's Patients: a Matter of Fibroblasts-Led Protumoral Microenvironment ?

PLoS One. 2015, Dec 22;10(12):e0145369.


Gendronneau G, Sanii S, Dang T, Deshayes F, Delacour D, Pichard E, Advedissian T, Sidhu SS, Viguier M,

Magnaldo T, Poirier F.

Overexpression of galectin-7 in mouse epidermis leads to loss of cell junctions and defective skin repair.

PLoS One. 2015, Mar 5;10(3):e0119031.


Wright AT, Magnaldo T, Sontag RL, Anderson LN, Sadler NC, Piehowski PD, Gache Y, Weber TJ.

Deficient expression of aldehyde dehydrogenase 1A1 is consistent with increased sensitivity of Gorlin

syndrome patients to radiation carcinogenesis.

Mol Carcinog., 2015, Jun;54(6):473-84.


2013


Rouanet S, Warrick E, Gache Y, Scarzello S, Avril MF, Bernerd F, Magnaldo T.

Genetic correction of stem cells in the treatment of inherited diseases and focus on xeroderma pigmentosum.

Int J Mol Sci., 2013, Oct 9;14(10):20019-36.


2012


Warrick E, Garcia M, Chagnoleau C, Chevallier O, Bergoglio V, Sartori D, Mavilio F, Angulo JF, Avril MF,

Sarasin A, Larcher F, Del Rio M, Bernerd F, Magnaldo T.

Preclinical corrective gene transfer in xeroderma pigmentosum human skin stem cells.

Mol. Ther., 2012, Apr;20(4):798-807.


2011


Villeneuve C, Baricault L, Canelle L, Barboule N, Racca C, Monsarrat B, Magnaldo T, Larminat F.

Mitochondrial proteomic approach reveals galectin-7 as a novel BCL-2 binding protein in human cells.

Mol Biol Cell., 2011, Apr;22(7):999-1013.


2010


Valin A, Avril MF, Magnaldo T.

Dermal fibroblasts exert a key influence in the development of basal-cell skin cancers: the model of

Gorlin syndrome.

Med Sci (Paris), 2010, Jan;26(1):22-5.


2009


Valin, A., Barnay-Verdier, S., Robert, T., Ripoche, H., Brellier, F., Chevallier-Lagente, O., Avril, M. F., Magnaldo, T.

PTCH +/- dermal fibroblasts isolated from healthy skin biopsy of Gorlin syndrome patients exhibit features

of carcinoma associated fibroblasts.

Plos One, 2009, 4(3):e4818.


Demers M, Couillard J, Giglia-Mari G, Magnaldo T, St-Pierre Y.

Increased galectin-7 gene expression in lymphoma cells is under the control of DNA methylation.

Biochem Biophys Res Commun. 2009 Sep 25;387(3):425-9.


2008


Gendronneau G., SS. Sidhu, S., Delacour D., Dang T., Calonne C., Houzelstein, D., Magnaldo, T.,

Poirier, F.

Galectin-7 in the control of epidermal homeostasis after injury.

Mol. Biol. Cell, 2008, Dec;19(12):5541-9.


Brellier, F., Bergoglio, V., Valin, A., Barnay, S., Chevallier-Lagente, O., Viel, P., Spatz, A., Gorry, P., Avril, M.,

Magnaldo, T.

Heterozygous mutations in the tumor suppressor gene PATCHED provoke basal cell carcinoma-like features in

human organotypic skin cultures

Oncogene, 2008, Nov20;27(51):6601-6.


Frechet, M., Warrick, E., Vioux, C., Chevallier O, Spatz, A., Benhamou, S., Sarasin, A., Bernerd, F., Magnaldo, T.

Over expression of matrix metalloproteinase 1 in dermal fibroblasts from DNA repair

deficient / cancer prone xeroderma pigmentosum group C patients,

Oncogene, 2008, Sept4;27(39):5223 - 32.


Brellier, F., Valin, A., Chevallier-Lagente, O., Gorry, P., Avril, M-F., Magnaldo, T.

Ultraviolet responses of Gorlin syndrome primary skin cells.

Br J. Dermatol., 2008, Aug:159(2):445-452.


Bergoglio, V., Emilie Warrick, E., Chevallier-Lagente, O., Magnaldo, T.

Cutaneous gene therapy : the graft takes / Thérapie génique cutanée : la greffe prend.

Med/Sci (Paris), 2008, 24, 607-14.


Warrick E, Bergoglio V, Bernerd F, Magnaldo T.

Epidermal stem cells and ex vivo cutaneous gene therapy: application to xeroderma pigmentosum

J Soc Biol. 2008;202(1):33-41.


2007


Bergoglio, V., Larcher, F., Chevallier-Lagente, O., Bernheim, A., Danos, O., Sarasin, A, Del Rio, M.D.,

Magnaldo, T.

Safe Selection of Genetically Manipulated Human Primary Keratinocytes with Very High Growth Potential

Using CD24.

Mol. Therapy., 2007, Dec;15(12):2186-93.


Dennler S, André J, Alexaki I, Li A, Magnaldo T, ten Dijke P, Wang XJ, Verrecchia F, Mauviel A.

Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation

of Gli2 and Gli1 expression in vitro and in vivo.

Cancer Res., 2007, Jul 15;67(14):6981-6.


Magnaldo T.

Suntanning and p53.

Med Sci (Paris), 2007, Jun-Jul;23(6-7):581-3.


Demers M, Biron-Pain K, Hébert J, Lamarre A, Magnaldo T, St-Pierre Y.

Galectin-7 in lymphoma: elevated expression in human lymphoid malignancies and decreased lymphoma

dissemination by antisense strategies in experimental model.

Cancer Res., 2007, Mar15;67(6):2824-9.


Gosselet FP, Magnaldo T, Culerrier RM, Sarasin A, Ehrhart JC.

BMP2 and BMP6 control p57(Kip2) expression and cell growth arrest/terminal differentiation in

normal primary human epidermal keratinocytes.

Cell Signal., 2007, Apr;19(4):731-9.


2006


Groisman, R., Kuraoka, I.,Chevallier, O., Gaye, N., Magnaldo,T., Tanaka, K., Harel-Bellan, A., Kisselev, AF.,

Y Nakatani

CSA-dependent degradation of CSB by the ubiquitin-proteasome pathway establishes a link between

complementation factors of the Cockayne syndrome.

Genes Dev., 2006, Jun1;20(11):1429-34.


Pruvost-Balland C, Gorry P, Boutet N, Magnaldo T, Mamelle G, Margulis A, Kolb F, Duvillard P,

Spatz A, Brugières L, Chompret A, Avril MF.

Clinical and genetic study in 22 patients with basal cell nevus syndrome.

Ann Dermatol Venereol., 2006, Feb;133(2):117-23. Review. 


Bergoglio V, Magnaldo T.

Nucleotide excision repair and related human diseases.

Genome Dyn., 2006;1:35-52.


Fréchet M, Bergoglio V, Chevallier-Lagente O, Sarasin A, Magnaldo T.

Complementation assays adapted for DNA repair-deficient keratinocytes.

Methods Mol Biol., 2006;314:9-23.


2005


Demers M, Magnaldo T, St-Pierre Y.

A novel function for galectin-7: promoting tumorigenesis by up-regulating MMP-9 gene expression.

Cancer Res., 2005, Jun 15;65(12):5205-10.


Reconstruction of DNA repair-deficient xeroderma pigmentosum skin in vitro: a model to study

hypersensitivity to UV light.

Bernerd F, Asselineau D, Frechet M, Sarasin A, Magnaldo T.

Photochem Photobiol., 2005, Jan-Feb;81(1):19-24.


2004


Brellier, F., Marionnet, C., Chevallier-Lagente, O., Toftgard, R., Mauviel, A., Sarasin, A., Magnaldo, T.

Ultraviolet radiation represses PATCHED transcription in human epidermal keratinocytes through an

AP1-depedent process.

Cancer Res., 2004, 64, 2699-2704.


Magnaldo, T.

Xeroderma pigmentosum: from genetics to hopes and realities of cutaneous gene therapy.

Expert. Opin. Biol. Ther., 2004, 4, 169-179.


Magnaldo T, Sarasin A.

Xeroderma pigmentosum: from symptoms and genetics to gene-based skin therapy.

Cells Tissues Organs. 2004;177(3):189-98. Review.


Magnaldo T.

The "war" of NER (nucleotide excision repair.

Med Sci (Paris), 2004, Mar;20(3):268-70.


Storan MJ, Magnaldo T, Biol-N'Garagba MC, Zick Y, Key B.

Expression and putative role of lactoseries carbohydrates present on NCAM in the rat primary

olfactory pathway.

J Comp Neurol., 2004, Jul 26;475(3):289-302.


& 2003 & 2002



(Feb 2016)


Financial Grants

Financial Grants