Robert Ballotti

University of Nice-Sophia Antipolis, Nice, Provence-Alpes-Côte d'Azur, France

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Publications (144)815.35 Total impact

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    ABSTRACT: Enhancer of Zeste homologue 2 (EZH2) belongs to the polycomb repressive complex 2 and catalyzes the methylation of histone H3 lysine 27. These pivotal epigenetic marks are altered in many cancers, including melanoma, as a result of EZH2 overexpression. Here, we show that the non-canonical-NF-kB pathway accounts for most of the NF-kB activity in melanoma cells, in contrast to non-cancer cells. We identify the non-canonical-NF-kB pathway as a key regulator of EZH2 expression in melanoma. We show a striking correlation between NF-kB2 and EZH2 expression in human melanoma metastases. We demonstrate that inhibition of the non-canonical NF-kB pathway by targeting NF-kB2/p52 or the upstream kinase NIK restores the senescence program in melanoma cells through the decrease of EZH2. On the contrary, the overexpression of NF-kB2/p52 in normal human melanocytes prevents stress- and oncogene-induced senescence. Finally, we show in mouse models that the inhibition of the non-canonical NF-kB pathway restores senescence and induces a dramatic reduction in tumor growth compared with controls, thus providing potential drug targets for the re-induction of senescence in melanoma and other cancers where EZH2 is overexpressed.Oncogene advance online publication, 14 September 2015; doi:10.1038/onc.2015.331.
    Oncogene 09/2015; DOI:10.1038/onc.2015.331 · 8.46 Impact Factor
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    ABSTRACT: Vitiligo affects 1% of the worldwide population. Halting disease progression and repigmenting the lesional skin represent the two faces of therapeutic challenge in vitiligo. We performed transcriptome analysis on lesional, perilesional, and non-depigmented skin from vitiligo patients and on matched skin from healthy subjects. We found a significant increase in CXCL10 in non-depigmented and perilesional vitiligo skin compared to levels in healthy control skin; however, neither CXCL10 nor other immune factors were deregulated in depigmented vitiligo skin. Interestingly, the WNT pathway, which is involved in melanocyte differentiation, was altered specifically in vitiligo skin. We demonstrated that oxidative stress decreases WNT expression/activation in keratinocytes and melanocytes. We developed an ex vivo skin model and confirmed the decrease activation of the WNT pathway in human skin subjected to oxidative stress. Finally, using pharmacological agents that activate the WNT pathway, we treated ex vivo depigmented skin from vitiligo patients and successfully induced differentiation of resident stem cells into pre-melanocytes. Our results shed light on the previously unrecognized role of decreased WNT activation in the preventionof melanocyte differentiation in depigmented vitiligo skin. Furthermore, these results support further clinical exploration of WNT agonists to repigment vitiligo lesions.Journal of Investigative Dermatology accepted article preview online, 31 August 2015. doi:10.1038/jid.2015.335.
    Journal of Investigative Dermatology 08/2015; DOI:10.1038/jid.2015.335 · 7.22 Impact Factor
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    ABSTRACT: Findings of increased vascularization in melasma lesions and hyperpigmentation in acquired bilateral telangiectatic macules suggested a link between pigmentation and vascularization. Using high-magnification digital epiluminescence dermatoscopy, laser confocal microscopy, and histological examination, we showed that benign vascular lesions of the skin have restricted but significant hyperpigmentation compared to the surrounding skin. We then studied the role of microvascular endothelial cells in regulating skin pigmentation using an in vitro co-culture model using endothelial cells and melanocytes. These experiments showed that endothelin 1 released by microvascular endothelial cells induces increased melanogenesis signaling, characterized by microphthalmia-associated transcription factor phosphorylation and increased tyrosinase and dopachrome tautomerase levels. Immunostaining for endothelin 1 in vascular lesions confirmed the increased expression on the basal layer of the epidermis above small vessels compared to perilesional skin. Endothelin acts through the activation of endothelin receptor B and the MAPKs, ERK1/2 and p38, to induce melanogenesis. Finally, culturing of reconstructed skin with microvascular endothelial cells led to increased skin pigmentation that could be prevented by inhibiting EDNRB. Taken together these results demonstrated the role of underlying microvascularization in skin pigmentation, a finding that could open new fields of research for regulating physiological pigmentation and for treating pigmentation disorders such as melasma.Journal of Investigative Dermatology accepted article preview online, 26 August 2015. doi:10.1038/jid.2015.332.
    Journal of Investigative Dermatology 08/2015; DOI:10.1038/jid.2015.332 · 7.22 Impact Factor
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  • Robert Ballotti
    Future Oncology 06/2015; 11(11):1587-90. DOI:10.2217/fon.15.24 · 2.48 Impact Factor
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    ABSTRACT: To identify 'melanoma-specific' microRNAs (miRNAs) we used an unbiased microRNA profiling approach to comprehensively study cutaneous melanoma in relation to other solid malignancies, which revealed 233 differentially expressed (≥ 2 fold, p < 0.05) miRNAs. Among the top 20 most significantly different miRNAs was hsa-miR-514a-3p. miR-514a is a member of a cluster of miRNAs (miR-506-514) involved in initiating melanocyte transformation and promotion of melanoma growth. We found miR-514a was expressed in 38/55 (69%) melanoma cell lines but in only 1/34 (3%) other solid cancers. To identify miR-514a regulated targets we conducted a miR-514a-mRNA 'pull-down' experiment, which revealed hundreds of genes, including: CTNNB1, CDK2, MC1R, and NF1, previously associated with melanoma. NF1 was selected for functional validation because of its recent implication inacquired resistance to BRAFV600E-targeted therapy. Luciferase-reporter assays confirmed NF1 as a direct target of miR-514a and over-expression of miR-514a in melanoma cell lines inhibited NF1 expression, which correlated with increased survival of BRAFV600E cells treated with PLX4032. These data provide another mechanism for the dysregulation of the MAPK pathway which may contribute to the profound resistance associated with current RAF-targeted therapies.
    Oncotarget 04/2015; 6(19). DOI:10.18632/oncotarget.3924 · 6.36 Impact Factor
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    ABSTRACT: Neurofibromatosis type 1 (NF1) is a frequent genetic disease leading to the development of Schwann cell-derived neurofibromas or melanocytic lesions called café-au-lait macules (CALMs). The molecular mechanisms involved in CALMs formation remain largely unknown. In this report, we show for the first time pathophysiological mechanisms of abnormal melanocyte differentiation in a human NF1(+/-) induced pluripotent stem cell (iPSC)-based model. We demonstrate that NF1 patient-derived fibroblasts can be successfully reprogrammed in NF1(+/-) iPSCs with active RAS signaling and that NF1 loss induces senescence during melanocyte differentiation as well as in patient's-derived CALMs, revealing a new role for NF1 in the melanocyte lineage. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Pigment Cell & Melanoma Research 03/2015; 28(4). DOI:10.1111/pcmr.12369 · 4.62 Impact Factor
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    ABSTRACT: It can be useful to assess the NRAS mutation status in patients with metastatic melanoma because NRAS-activating mutations confer resistance to RAF inhibitors, and NRAS-mutated patients appear to be sensitive to mitogen-activated protein kinase (MEK) inhibitors. We aimed to assess the diagnostic accuracy of an immunohistochemistry (IHC) approach using a novel anti-NRAS (Q61R) monoclonal antibody on formalin-fixed paraffin-embedded tissue samples from patients with metastatic melanoma. We conducted a retrospective multicenter cohort study on 170 patients with metastatic melanoma. The automated IHC assay was performed using the SP174 clone, and compared with results of the molecular testing. Evaluation of a test cohort with knowledge of the mutation status established a specific IHC pattern for the mutation. In the independent blinded analysis of the remaining cases, the anti-NRAS (Q61R) antibody accurately identified all NRAS Q61R-mutated tumors, and demonstrated 100% sensitivity and specificity. Limitations include retrospective design and lack of multicenter interobserver reproducibility. The NRAS (Q61R) IHC assay is reliable and specific for the evaluation of the Q61R mutation status in metastatic melanoma and may be an alternative to molecular biology in evaluation of metastatic melanoma in routine practice. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
    Journal of the American Academy of Dermatology 02/2015; 72(5). DOI:10.1016/j.jaad.2015.01.012 · 4.45 Impact Factor
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    ABSTRACT: Understanding the molecular and cellular processes underlying melanoma plasticity and heterogeneity is of paramount importance to improve the efficiency of current treatment and to overcome resistance to chemotherapy drugs. The notion of plasticity and heterogeneity implies the existence of melanoma cell populations with different phenotypic and tumorigenic properties. Using melanoma cell lines and melanoma cells freshly isolated from patient biopsies, we investigated the relationship between ABCB5+, CD271+ and low-MITF, expressing populations that were reported to display melanoma initiating cell properties. Here, we showed that ABCB5+ and CD271+ populations poorly overlap. However, we found that the CD271+ population is enriched in low-MITF cells and expresses a higher level of stemness genes, such as OCT4, NANOG and NES. These features could explain the increased tumorigenicity of the CD271+ cells. The rapid conversion of CD271+ to CD271− cells in vitro demonstrates the plasticity ability of melanoma cells. Finally, we observed that the transient slow-growing population contains only CD271+ cells that are highly tumorigenic. However, the fast growing/CD271+ population exhibits a poor tumorigenic ability. Taking together, our data show that CD271 is an imperfect marker for melanoma initiating cells, but may be useful to identify melanoma cells with an increased stemness and tumorigenic potential.
    Oncotarget 07/2014; 5(14):5272-5283. DOI:10.18632/oncotarget.1967 · 6.36 Impact Factor
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    Michael Cerezo · Tijana Tomic · Robert Ballotti · Stéphane Rocchi
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    ABSTRACT: Metformin is the most widely used antidiabetic drug that belongs to the biguanide class. It is very well-tolerated and has the major clinical advantage of not inducing hypoglycemia. Metformin decreases hepatic glucose production via a mechanism requiring liver kinase B1, which controls the metabolic checkpoint, AMP-activated protein kinase-mammalian target of rapamycin and neoglucogenic genes. The effects of metformin on this pathway results in reduced protein synthesis and cell proliferation. These observations have given the impetus for many investigations on the role of metformin in the regulation of tumor cell proliferation, cell cycle regulation, apoptosis and autophagy. Encouraging results from these studies have shown that metformin could potentially be used as an efficient anticancer drug in various neoplasms such as prostate, breast, lung, pancreas cancers and melanoma. These findings are strengthened by retrospective epidemiological studies that have found a decrease in cancer risk in diabetic patients treated with metformin. In this review, we have focused our discussion on recent the molecular mechanisms of metformin that have been described in various solid tumors in general, and in melanoma in particular. This article is protected by copyright. All rights reserved.
    Pigment Cell & Melanoma Research 05/2014; 28(1). DOI:10.1111/pcmr.12267 · 4.62 Impact Factor
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    ABSTRACT: Several reports have demonstrated inhibitory effect of metformin, a widely used drug in treatment of type 2 diabetes, on the proliferation of many cancers including melanoma. Recently it has been shown that metformin is able to modulate cAMP level in liver. Since, cAMP plays a crucial role in melanin synthesis and skin pigmentation, we investigated the effect of metformin on melanogenesis both in vitro and in vivo. We showed that metformin led to reduced melanin content in melanoma cells and in normal human melanocytes by decreasing cAMP accumulation and CREB phosphorylation. This inhibitory effect is correlated with decreased expression of master genes of melanogenesis, MITF, Tyrosinase, DCT and TRP1. Furthermore, we demonstrated that the anti-melanogenic effect of metformin is independent of AMPK pathway. Interestingly, topically application of metformin induced tail whitening in mice. Finally, we confirmed the anti-melanogenesis effect of metformin on reconstituted human epidermis and on human skin biopsies. These data emphasize the depigmenting effect of metformin and suggest a clinical strategy for using metformin in topical treatment of hyperpigmentation disorders.Journal of Investigative Dermatology accepted article peview online, 22 April 2014. doi:10.1038/jid.2014.202.
    Journal of Investigative Dermatology 04/2014; 134(10). DOI:10.1038/jid.2014.202 · 7.22 Impact Factor
  • H. Montaudié · C. Bertolotto · R. Ballotti · T. Passeron
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    ABSTRACT: El color de la piel es el resultado de una sutil mezcla de pigmentos melánicos producidos por células especializadas, los melanocitos, cuyo origen embriológico es el tubo neural. En la piel, los melanocitos se localizan en la capa basal de la epidermis y en el bulbo piloso. La melanogénesis representa el mecanismo que da lugar a la síntesis de melanina, la cual se efectúa en el seno de una organela intracitoplasmática, de la familia de los lisosomas secretores, llamada «melanosoma». Se producen dos familias de melaninas: la eumelanina, de color marrón o negro, y la feomelanina, de color amarillo o rojo anaranjado, que es menos fotoprotectora. Se han identificado tres enzimas principales de la melanogénesis: la tirosinasa y las proteínas relacionadas con la tirosinasa 1 y 2. Un número importante de genes controla la embriogénesis de los melanocitos, la biogénesis de los melanosomas, su transporte en los melanocitos y su paso a los queratinocitos. Se han identificado numerosos factores de regulación de la melanogénesis (ultravioletas, hormonas melanotrópicas, citocinas, etc.). Se han analizado progresivamente los mecanismos de señalización celular implicados en la melanogénesis. Estos conocimientos recientes permitirán conocer mejor las bases genéticas de la fotoprotección melánica de la piel. Han permitido identificar numerosas dianas potenciales para futuras estrategias terapéuticas de la hipermelanosis y la hipomelanosis cutáneas.
    03/2014; 48(1):1–11. DOI:10.1016/S1761-2896(14)66800-X
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    ABSTRACT: SIRT1 operates as both a tumor suppressor and oncogenic factor depending on the cell context. Whether SIRT1 plays a role in melanoma biology remained poorly elucidated. Here, we demonstrate that SIRT1 is a critical regulator of melanoma cell proliferation. SIRT1 suppression by genetic or pharmacological approaches induces cell cycle arrest and a senescence-like phenotype. Gain and loss of function experiments show that M-MITF regulates SIRT1 expression, thereby revealing a melanocyte-specific control of SIRT1. SIRT1 over-expression relieves the senescence-like phenotype and the proliferation arrest caused by MITF suppression, demonstrating that SIRT1 is an effector of MITF-induced proliferation in melanoma cells. Interestingly, SIRT1 level and activity are enhanced in the PLX4032-resistant BRAFV600E-mutated melanoma cells compared with their sensitive counterpart. SIRT1 inhibition decreases melanoma cell growth and rescues the sensibility to PLX4032 of PLX4032-resistant BRAFV600E-mutated melanoma cells. In conclusion, we provide the first evidence that inhibition of SIRT1 warrants consideration as an anti-melanoma therapeutic option.
    Oncotarget 02/2014; 5(8). DOI:10.18632/oncotarget.1791 · 6.36 Impact Factor
  • Journal of Investigative Dermatology 12/2013; 134(5). DOI:10.1038/jid.2013.525 · 7.22 Impact Factor
  • Annales de Dermatologie et de Vénéréologie 12/2013; 140(12):S646. DOI:10.1016/j.annder.2013.09.616 · 0.92 Impact Factor
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    Journal of dermatological science 11/2013; 73(3). DOI:10.1016/j.jdermsci.2013.11.003 · 3.42 Impact Factor
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    ABSTRACT: Here, we showed that the secretome of senescent melanoma cells drives basal melanoma cells towards a mesenchymal phenotype, with characteristic of stems illustrated by increased level of the prototype genes FN1, SNAIL, OCT4 and NANOG. This molecular reprogramming leads to an increase in the low-MITF and slow-growing cell population endowed with melanoma-initiating cell features. The secretome of senescent melanoma cells induces a panel of 52 genes, involved in cell movement and cell/cell interaction, among which AXL and ALDH1A3 have been implicated in melanoma development. We found that the secretome of senescent melanoma cells activates the STAT3 pathway and STAT3 inhibition prevents secretome effects, including the acquisition of tumorigenic properties. Collectively, the findings provide insights into how the secretome of melanoma cells entering senescence upon chemotherapy treatments increases the tumorigenicity of naïve melanoma cells by inducing, through STAT3 activation, a melanoma-initiating cell phenotype that could favor chemotherapy resistance and relapse.
    Oncotarget 08/2013; 4(12). DOI:10.18632/oncotarget.1143 · 6.36 Impact Factor
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    ABSTRACT: BRAF is the most prevalent oncogene and an important therapeutic target in melanoma. In some cancers BRAF is activated by rearrangements that fuse its kinase domain to 5' partner genes. We examined 848 comparative genomic hybridization profiles of melanocytic tumors and found copy number transitions within BRAF in 10 tumors, of which six could be further characterized by sequencing. In all, the BRAF kinase domain was fused in-frame to six different N-terminal partners. No other mutations were identified in melanoma oncogenes. One of seven melanoma cell lines without known oncogenic mutations harbored a similar BRAF fusion, which constitutively activated the MAP-kinase pathway. Sorafenib, but not vemurafenib, could block MAP-kinase pathway activation and proliferation of the cell line at clinically relevant concentrations, whereas BRAF(V) (600E) mutant melanoma cell lines were significantly more sensitive to vemurafenib. The patient from whom the cell line was derived showed a durable clinical response to sorafenib. This article is protected by copyright. All rights reserved.
    Pigment Cell & Melanoma Research 07/2013; 26(6). DOI:10.1111/pcmr.12148 · 4.62 Impact Factor
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    Robert Ballotti
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    ABSTRACT: As a young researcher, I was working on insulin receptor signaling and seeking my way in the maze of basic research. In fact, I was fascinated by melanocytes and skin pigmentation but my knowledge in the field was minimal. Living in Nice and being a fan of seaside leisure, I knew that exposure to sunlight leads to a beautiful golden pigmentation of the skin, commonly known as tanning. I also knew that tanning was due to pigments being synthesized by specialized cells called melanocytes. This article is protected by copyright. All rights reserved.
    Pigment Cell & Melanoma Research 07/2013; 27(1). DOI:10.1111/pcmr.12142 · 4.62 Impact Factor
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    ABSTRACT: Metformin was reported to inhibit the proliferation of many cancer cells including melanoma cells. In this report, we investigated the effect of metformin on melanoma invasion and metastasis development. Using different in vitro approaches, we found that metformin inhibits cell invasion without affecting cell migration and independently of anti-proliferation action. This inhibition is correlated with modulation of expression of proteins involved in epithelial mesenchymal transition such as Slug, Snail, SPARC, fibronectin and N-Cadherin and with inhibition of MMP-2 and MMP-9 activation. Further our data indicate that this process is dependent of activation of AMPK and tumor suppressor protein, p53. Finally, we demonstrated that metformin inhibits melanoma metastasis development in mice using extravasation and metastasis models. The presented data reinforce the fact that metformin might be a good candidate for clinical trial in melanoma treatment.
    Molecular Cancer Therapeutics 06/2013; 12(8). DOI:10.1158/1535-7163.MCT-12-1226-T · 5.68 Impact Factor

Publication Stats

5k Citations
815.35 Total Impact Points


  • 2000–2015
    • University of Nice-Sophia Antipolis
      • Faculty of Medicine
      Nice, Provence-Alpes-Côte d'Azur, France
  • 1989–2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1987–2010
    • French Institute of Health and Medical Research
      • • Mediterranean Center for Molecular Medicine C3M
      • • Institute of Genetics and Molecular and Cellular Biology
      Lutetia Parisorum, Île-de-France, France
  • 2003
    • Leiden University Medical Centre
      Leyden, South Holland, Netherlands
  • 1988
    • Bispebjerg Hospital, Copenhagen University
      København, Capital Region, Denmark