Background and Previous activities
Vitiligo is an acquired, idiopathic disorder characterized by circumscribed depigmented macules and patches. Vitiligo affects approximately 0.5–2% of the general population worldwide, and it may appear any time from shortly after birth to old-age. Although limited to skin defects, vitiligo has a strong impact on the quality of life of affected people. It has been demonstrated that the impact of vitiligo on professional, social and sexual life is higher than in diabetes, depression, or even some cancers. Thus, vitiligo induces a strong therapeutic demand from affected people but unfortunately actual treatments are far to give truly satisfactory results. Vitiligo is a multifactorial disorder related to both genetic and nongenetic factors. It is generally agreed that there is an absence of functional melanocytes in vitiligo skin and that this loss of histochemically recognizable melanocytes is the result of their destruction. Recent advances showed the crucial role of the immune system in the pathophysiology of this disorder. However, the main problem is to stimulate the proliferation and the differentiation of melanoblasts to repigment the affected areas but the mechanisms involved in such phenomenon remain poorly understood and modest responses are obtained with the actual therapeutic approaches.
The transformation of melanocytic cells is responsible for melanoma, one of the deadliest cancers when it gets to a metastatic stage. The increased incidence of melanoma was higher in the past 10 years than all other cancers except for the lung cancer in women. Its incidence doubles every 10 years and keeps on growing of 5% a year in Caucasian population. Recent advances showed the heterogeneity of melanomas. Depending on the type and localization of melanomas several mutations have been described. Melanoma is highly resistant to radiotherapy and the rate of response to chemotherapies is low and usually is limited in time. Immunotherapy and vaccination protocols give inconsistent results. Therapies targeting activated pathways recently showed encouraging results but resistances developed under this approach and lead to a secondary progression of the disease. Those data urge the need for other therapeutic approaches. The approaches aiming to enhance the differentiation of cancer cells by using retinoic acid and derivatives, although useful in some leukemia and solid cancers, did not show any efficacy in melanoma. A protein, named PRAME, was initially described as a melanoma antigen. PRAME was then reported to be expressed by several solid cancers. PRAME works as an antagonist of the receptor of retinoic acid. Its inhibition restored the sensitivity to retinoic acid. The strong expression of PRAME in most of the melanoma cells probably explains the high resistance of those tumors to retinoic acid treatments.
The importance to better understand the mechanisms of the melanocytic proliferation and differentiation appears clearly. The study of the signaling pathways that regulate those mechanisms should allow identifying new therapeutic targets to regulate melanogenesis and melanocyte differentiation, but also to decrease the proliferation and to play on the differentiation of melanoma cells.
Keeping in mind those objectives we studied the role of the transcriptional factor called SOX9 in melanocytic cells. We first demonstrated that SOX9 is expressed in vitro and in vivo by the melanocytes of the skin and plays a key role in the UVB induced pigmentation. Activated by the cyclic AMP and protein kinase A (PKA), SOX9 increases the expression of the enzymes responsible for the melanogenesis by acting directly on the transcriptional factor MITF. This finally increases the production of melanin within the melanosomes. We also demonstrated that Agouti Signaling Protein (ASP) already known to inhibit the melanogenesis, is able to decrease the expression of SOX9 in melanocytes. This action can explain, at least partially, the still poorly understood mechanism of action of ASP.
Then, we further studied the expression and the role of SOX9 in melanoma cells. We demonstrated that the expression of SOX9 was decreased in most of advanced human melanoma samples. We showed that SOX9 inhibits the proliferation of melanoma cells by acting indirectly (through MITF) but also directly on the p21 promoter. We also demonstrated that SOX9 can restore the sensitivity to retinoic acid by decreasing the expression of the PRAME protein. The over expression of SOX9 strongly reduces the tumorigenicity of melanoma cells in vivo in mouse models and ex vivo in human reconstructed skins. We finally showed that agents capable of increasing the expression and/or activating SOX9, such as the prostaglandin D2 (PGD2) could reproduce its action on the proliferation of melanoma cells and also restore their sensitivity to retinoic acid.
Thus, the use of topical agents capable of regulating SOX9 (including prostaglandins) appears of great interest for treating pigmentary disorders. Such agents could be used to differentiate the melanocyte stem cells and to promote the repigmentation of vitiligo lesions. Concomitantly, the major effect of SOX9 on the proliferation of melanoma cells and its capability to restore retinoic acid sensitivity offer combined therapeutic perspectives not only for melanoma but also to most solid cancers that are resistant to retinoic acid.
Our project aims studying the mechanisms of differentiation of the melanocytic cells with a special focus on vitiligo and melanoma. By using the unique opportunity to work with patient’s samples, we would like to dissect the mechanisms responsible for the differentiation of melanocytes. The ultimate goal is to identify agents that could be used in clinical practice to treat pigmentary disorders and melanoma.
A) Study of the mechanisms involved in the repigmentation of the vitiligo lesions
In vitiligo lesions, the melanocytes are no longer present in the epidermis, however some treatments (mostly UV) can promote the differentiation of melanoblasts to melanocytes that can re-colonize the skin and repigment the affected lesions. The mechanisms implicated in the differentiation of melanocyte stem cells are still poorly understood. Identifying those mechanisms could have a huge impact on the treatment of the vitiligo.
We are using transcriptional analysis of skin samples of vitiligo patients to better understand the mechanisms involved in the pathogenesis of vitiligo and in the differentiation and proliferation of melanocytes progenitors under treatment. We use ex vivo models to test the effects of selected molecules and then dissect the pathways involved. Identifying such molecules could be used for repigmented affected skin of vitiligo patients.
B) Study of the redifferentiation of melanoma cells
We are studying the regulation of PRAME and other proteins involved in the resistance of melanoma cells to retinoic acid. We are testing the optimal combination of agents capable of decreasing this resistance and agonists of retinoic acid receptor to reach an optimal effect on melanoma proliferation.
We are also studying the effect of PGD2 derivatives on melanoma proliferation and differentiation and dissect the pathways involved in those processes.
All those experiments are made on melanoma cells line but also on melanoma cells freshly extracted from melanoma patients for a best accuracy in the results. Then agents are finally tested in murine models.
The restoration of the sensitivity to retinoic acid derivatives, could allow targeting all the cancer cells and forcing them to stop their proliferation and to redifferentiate. If we succeed, we will have a potential curative approach, not only for melanoma but for most of the solid cancers.
Micro holes for delivering melanocytes into the skin: an ex vivo approach
Regazzetti C, Alcor D, Chignon-Sicard B, Passeron T
Pigment Cell Melanoma Res 2016 Jul;29(4):481-3 PMID : 27172992
NF-kB2 induces senescence bypass in melanoma via a direct transcriptional activation of EZH2
De Donatis GM, Pape EL, Pierron A, Cheli Y, Hofman V, Hofman P, Allegra M, Zahaf K, Bahadoran P, Rocchi S, Bertolotto C, Ballotti R, Passeron T
Oncogene 2015 Sep; PMID : 26364600
Copper Bromide Laser vs Triple-Combination Cream for the Treatment of Melasma: A Randomized Clinical Trial
Hammami Ghorbel H, Boukari F, Fontas E, Montaudié H, Bahadoran P, Lacour JP, Passeron T
JAMA Dermatol 2015 Jul;151(7):791-2 PMID : 25715311
Transcriptional Analysis of Vitiligo Skin Reveals the Alteration of WNT Pathway: A Promising Target for Repigmenting Vitiligo Patients
Regazzetti C, Joly F, Marty C, Rivier M, Mehul B, Reiniche P, Mounier C, Rival Y, Piwnica D, Cavalié M, Chignon-Sicard B, Ballotti R, Voegel J, Passeron T
J. Invest. Dermatol. 2015 Aug; PMID : 26322948
Endothelial Cells Promote Pigmentation Through Endothelin Receptor B Activation
Regazzetti C, De Donatis GM, Ghorbel HH, Cardot-Leccia N, Ambrosetti D, Bahadoran P, Chignon B, Lacour JP, Ballotti R, Mahns A, Passeron T
J. Invest. Dermatol. 2015 Aug; PMID : 26308584
Maintenance therapy of adult vitiligo with 0.1% tacrolimus ointment: a randomized, double blind, placebo-controlled study
Cavalié M, Ezzedine K, Fontas E, Montaudié H, Castela E, Bahadoran P, Taïeb A, Lacour JP, Passeron T
J. Invest. Dermatol. 2015 Apr;135(4):970-4 PMID : 25521460
New onset of articular inflammatory manifestations in patients with hidradenitis suppurativa under treatment with infliximab
Acquacalda E, Roux CH, Albert C, Breuil V, Passeron T, Euller-Ziegler L
Joint Bone Spine 2015 Mar; PMID : 25776450
Prevention of melasma relapses with sunscreen combining protection against UV and short wavelengths of visible light: a prospective randomized comparative trial
Boukari F, Jourdan E, Fontas E, Montaudié H, Castela E, Lacour JP, Passeron T
J. Am. Acad. Dermatol. 2015 Jan;72(1):189-90.e1 PMID : 25443629
Ultrasound study of entheses in psoriasis patients with or without musculoskeletal symptoms: A prospective study
Acquacalda E, Albert C, Montaudie H, Fontas E, Danre A, Roux CH, Breuil V, Lacour JP, Passeron T, Ziegler LE
Joint Bone Spine 2015 Jul;82(4):267-71 PMID : 25881759
Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata
Castela E, Le Duff F, Butori C, Ticchioni M, Hofman P, Bahadoran P, Lacour JP, Passeron T
JAMA Dermatol 2014 Jul;150(7):748-51 PMID : 24872229
Inhibition of melanogenesis by the antidiabetic metformin
Lehraiki A, Abbe P, Cerezo M, Rouaud F, Regazzetti C, Chignon-Sicard B, Passeron T, Bertolotto C, Ballotti R, Rocchi S
J. Invest. Dermatol. 2014 Oct;134(10):2589-97 PMID : 24756109
Interest of confocal laser scanning microscopy for the diagnosis and treatment monitoring of demodicosis
Harmelin Y, Delaunay P, Erfan N, Tsilika K, Zorzi K, Passeron T, Lacour JP, Bahadoran P
J Eur Acad Dermatol Venereol 2014 Feb;28(2):255-7 PMID : 23659565
Laser-assisted depigmentation for resistant vitiligo: a retrospective case series with long-term follow-up
Boukari F, Lacour JP, Ortonne JP, Bahadoran P, Passeron T
J Eur Acad Dermatol Venereol 2014 Mar;28(3):374-7 PMID : 23167541
PGJ2 restores RA sensitivity in melanoma cells by decreasing PRAME and EZH2
Pierron A, Le Pape E, Montaudié H, Castela E, De Donatis GM, Allegra M, Bertolotto C, Rocchi S, Cheli Y, Ballotti R, Passeron T
J. Dermatol. Sci. 2014 Mar;73(3):258-61 PMID : 24289988
Reflectance confocal microscopy features of Degos disease
Cavalié M, Tsilika K, Sillard L, Cardot-Leccia N, Passeron T, Lacour JP, Bahadoran P
JAMA Dermatol 2014 Jan;150(1):96-7 PMID : 23864231
Risk for nevus transformation and melanoma proliferation and invasion during natalizumab treatment: four years of dermoscopic follow-up with immunohistological studies and proliferation and invasion assays
Pharaon M, Tichet M, Lebrun-Frénay C, Tartare-Deckert S, Passeron T
JAMA Dermatol 2014 Aug;150(8):901-3 PMID : 24919481
Solar urticaria to visible light triggered by light-emitting diode therapy
Montaudié H, Lacour JP, Rostain G, Duteil L, Passeron T
J. Am. Acad. Dermatol. 2014 Sep;71(3):e74-5 PMID : 25128130
Treatment of linear and whorled hypermelanosis with Q-switched laser
Catherine S, Lacour JP, Passeron T
Dermatol Surg 2014 Sep;40(9):1044-6 PMID : 25099293
Treatment of port wine stains with pulsed dye laser and topical timolol: a multicenter randomized controlled trial
Passeron T, Maza A, Fontas E, Toubel G, Vabres P, Livideanu C, Mazer JM, Rossi B, Boukari F, Harmelin Y, Dreyfus I, Mazereeuw-Hautier J, Lacour JP
Br. J. Dermatol. 2014 Jun;170(6):1350-3 PMID : 24641096
Secondary hyperpigmentation during interferon alfa treatment for chronic hepatitis C virus infection
Tsilika K, Tran A, Trucchi R, Pop S, Anty R, Cardot-Leccia N, Lacour JP, Ortonne JP, Passeron T
JAMA Dermatol 2013 Jun;149(6):675-7 PMID : 23553009
Treatment of granuloma annulare with the 595-nm pulsed dye laser, a multicentre retrospective study with long-term follow-up
Passeron T, Fusade T, Vabres P, Bousquet-Rouaud R, Collet-Vilette AM, Dahan S, Toubel G
J Eur Acad Dermatol Venereol 2013 Jun;27(6):785-8 PMID : 22188443
Use of 2940-nm Erbium-Yag fractional laser for treating the skin texture changes in stabilized Parry Romberg syndrome
Ghorbel HH, Lacour JP, Passeron T
Eur J Dermatol 2013 Nov-Dec;23(6):908-9 PMID : 24446016