Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses

Jiang, Lin; Campagne, Cécile; Sundström, Elisabeth; Sousa, Pedro M.; Imran, Saima; Seltenhammer, Monika; Pielberg, Gerli; Olsson, Mats Joakim Robert; Egidy, Giorgia; Andersson, Leif; Golovko, Anna

doi:10.1186/1471-2407-14-857

Cited by 21 publications

(11 citation statements)

References 30 publications

(35 reference statements)

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“…Naturally occurring models include some horse breeds, for which aging is associated with graying of the coat color, mucosal melanomas and depigmentation. Melanoma development has been attributed to a mutation in the intron 6 of STX17 ( Rosengren Pielberg et al, 2008 ), leading to an activation of the ERK pathway ( Jiang et al, 2014 ). Dogs show a quite high incidence of melanoma, and different breeds can serve as models for multiple melanoma subtypes.…”

Section: Animal Models Of Melanomamentioning

confidence: 99%

The MeLiM Minipig: An Original Spontaneous Model to Explore Cutaneous Melanoma Genetic Basis

Bourneuf

2017

Front. Genet.

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Melanoma is the deadliest skin cancer and is a major public health concern with a growing incidence worldwide. As for other complex diseases, animal models are needed in order to better understand the mechanisms leading to pathology, identify potential biomarkers to be used in the clinics, and eventually molecular targets for therapeutic solutions. Cutaneous melanoma, arising from skin melanocytes, is mainly caused by environmental factors such as UV radiation; however a significant genetic component participates in the etiology of the disease. The pig is a recognized model for spontaneous development of melanoma with features similar to the human ones, followed by a complete regression and a vitiligo-like depigmentation. Three different pig models (MeLiM, Sinclair, and MMS-Troll) have been maintained through the last decades, and different genetic studies have evidenced a complex inheritance of the disease. As in humans, pigmentation seems to play a prominent role, notably through MC1R and MITF signaling. Conversely, cell cycle genes as CDKN2A and CDK4 have been excluded as predisposing for melanoma in MeLiM. So far, only sparse studies have focused on somatic changes occurring during oncogenesis, and have revealed major cytological changes and a potential dysfunction of the telomere maintenance system. Finally, the spontaneous tumor progression and regression occurring in these models could shed light on the interplay between endogenous retroviruses, melanomagenesis, and adaptive immune response.

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Section: Animal Models Of Melanomamentioning

confidence: 99%

The MeLiM Minipig: An Original Spontaneous Model to Explore Cutaneous Melanoma Genetic Basis

Bourneuf

2017

Front. Genet.

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“…Both STX17 and the neighbouring NR4A3 gene are overexpressed in melanomas from grey horses. It is known that the duplication in STX17 is strongly associated with constitutive activation of the ERK pathway in melanocytic cells from grey horses, highlighting the universal importance of the MAPK/ERK pathway in melanomagenesis . Further, experimental models using reporter constructs in transgenic zebrafish have demonstrated that the duplicated STX17 sequence acts as a strong enhancer in neural crest cells and has subsequent melanophore‐specific activity during embryonic development, consistent with the phenotypic manifestation of the mutation in horses .…”

Section: Using the Horse To Model Melanomamentioning

confidence: 80%

Cross‐species models of human melanoma

Weyden

Patton

Wood

et al. 2015

The Journal of Pathology

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Although transformation of melanocytes to melanoma is rare, the rapid growth, systemic spread, as well as the chemoresistance of melanoma present significant challenges for patient care. Here we review animal models of melanoma, including murine, canine, equine, and zebrafish models, and detail the immense contribution these models have made to our knowledge of human melanoma development, and to melanocyte biology. We also highlight the opportunities for cross‐species comparative genomic studies of melanoma to identify the key molecular events that drive this complex disease. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…In gray horses, a gene duplication in intron 6 of STX17 (synataxin 17) contributes a cis-acting regulatory mutation resulting in a very high incidence of EMM [28]. This gene duplication induces constitutive activation of the extracellular signal-regulated kinase (ERK) pathway and melanomagensis in EMM [29, 30]. The MEK-ERK signaling pathway regulates PD-L1 gene expression via crosstalk with inflammatory cytokine signaling including the IFN-γ-STAT1 pathway [31–33].…”

Section: Discussionmentioning

confidence: 99%

PD-L1 expression in equine malignant melanoma and functional effects of PD-L1 blockade

Ganbaatar

Konnai

Okagawa

et al. 2020

Preprint

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24 Programmed death-1 (PD-1) is an immunoinhibitory receptor expressed on exhausted T cells 25 during chronic illness. Interaction of PD-1 with its ligand PD-ligand 1 (PD-L1) delivers inhibitory 26 signals and impairs proliferation, cytokine production, and cytotoxicity of T cells. We reported 27 that the PD-1/PD-L1 pathway is closely associated with T-cell exhaustion and disease progression 28 in bovine chronic infections and canine tumors. Moreover, we found that blocking antibodies 29 targeting PD-1 and PD-L1 restore T-cell functions and may be used in immunotherapy in cattle 30 and dogs. However, the immunological role of the PD-1/PD-L1 pathway remains unclear for 31 chronic equine diseases, including tumors. In this study, we identified nucleotide sequences of 32 equine PD-1 (EqPD-1) and PD-L1 (EqPD-L1) and investigated the role of anti-bovine PD-L1 33 monoclonal antibodies (mAbs) against EqPD-L1 using in vitro assays. We also evaluated the 34 expression of PD-L1 in tumor tissues of equine malignant melanoma (EMM). 35The amino acid sequences of EqPD-1 and EqPD-L1 share a high identity and similarity with 36 homologs from other mammalian species. Two clones of the anti-bovine PD-L1 mAbs recognized 37 EqPD-L1 in flow cytometry, and one of these cross-reactive mAbs blocked the binding of equine 38 PD-1/PD-L1. Importantly, PD-L1 expression was confirmed in EMM tumor tissues by 39 immunohistochemistry. A cultivation assay revealed that PD-L1 blockade enhanced the 40 production of Th1 cytokines in equine immune cells.41 These results suggest that our anti-PD-L1 mAbs may be useful for investigating the expression 42 and role of the equine PD-1/PD-L1 pathway. Further research is required to discover the 43 immunological role of PD-1/PD-L1 in chronic equine diseases and elucidate a future application 44 in immunotherapy for horse. 45 Keywords: horse, PD-1, PD-L1, IFN-γ, T cells, chronic diseases, melanoma 3 46 Introduction 47 Programmed cell death-1 (PD-1) is an immunoinhibitory receptor, which is expressed on activated 48 and exhausted T cells [1]. Its ligand programmed death ligand 1 (PD-L1) is expressed on immune 49 cells, including antigen-presenting cells, and tumor cells [1]. The interaction of PD-1 and PD-L1 50 suppresses the activation signal mediated by T-cell receptors and inhibits effector functions of T 51 cells, such as cytokine production and cell proliferation [1]. This pathway is invaluable for 52 regulating excessive immune responses. In cancers, however, tumor cells utilize the suppression 53 of T cells mediated by PD-1/PD-L1 to avoid anti-tumor immune responses [1]. In human medicine, 54 the blocking antibodies targeting PD-1 or PD-L1 have been leveraged for treatment of various 55 types of cancers and resulted in remarkable outcomes with 20%-90% response rates in multiple 56 clinical trials [1].57 Equine malignant melanoma (EMM) is a common neoplasm among aged gray horses, which 58 results in dermal tumors at multiple sites [2]. A previous study reported that around 80% of aged 59 gray horses deve...

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Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses

Cited by 21 publications

References 30 publications

The MeLiM Minipig: An Original Spontaneous Model to Explore Cutaneous Melanoma Genetic Basis

The MeLiM Minipig: An Original Spontaneous Model to Explore Cutaneous Melanoma Genetic Basis

Cross‐species models of human melanoma

PD-L1 expression in equine malignant melanoma and functional effects of PD-L1 blockade

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