Tg(Grm1) transgenic mice: A murine model that mimics spontaneous uveal melanoma in humans?

Schiffner, Susanne; Braunger, Barbara M.; Jel, Miriam M. de; Coupland, Sarah E.; Tamm, Ernst R.; Bosserhoff, Anja‐Katrin

doi:10.1016/j.exer.2014.07.009

Cited by 35 publications

(40 citation statements)

References 30 publications

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“…To conclude, the genetically engineered zebrafish UM model we describe here joins the genetically engineered mouse models [35, 41, 42] as invaluable in vivo platforms for establishing the molecular drivers of UM. Particular strengths of our zebrafish system are the parallels with human UM development, technical simplicity, low cost with which genetic modification can be achieved, as well as the ability to segregate benign and malignant stages of neoplastic progression that should facilitate identification of genetic and epigenetic changes propelling this transition.…”

Section: Discussionmentioning

confidence: 99%

Minimal contribution of ERK1/2-MAPK signalling towards the maintenance of oncogenic GNAQQ209P-driven uveal melanomas in zebrafish

et al. 2016

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Mutations affecting Gαq proteins are pervasive in uveal melanoma (UM), suggesting they ‘drive’ UM pathogenesis. The ERK1/2-MAPK pathway is critical for cutaneous melanoma development and consequently an important therapeutic target. Defining the contribution of ERK1/2-MAPK signalling to UM development has been hampered by the lack of an informative animal model that spontaneously develops UM. Towards this end, we engineered transgenic zebrafish to express oncogenic GNAQQ209P in the melanocyte lineage. This resulted in hyperplasia of uveal melanocytes, but with no evidence of malignant progression, nor perturbation of skin melanocytes. Combining expression of oncogenic GNAQQ209P with p53 inactivation resulted in earlier onset and even more extensive hyperplasia of uveal melanocytes that progressed to UM. Immunohistochemistry revealed only weak immunoreactivity to phosphorylated (p)ERK1/2 in established uveal tumours—in contrast to strong immunoreactivity in oncogenic RAS-driven skin lesions—but ubiquitous positive staining for nuclear Yes-associated protein (YAP). Moreover, no changes were observed in pERK1/2 levels upon transient knockdown of GNAQ or phospholipase C-beta (PLC-β) inhibition in the majority of human UM cell lines we tested harbouring GNAQ mutations. In summary, our findings demonstrate a weak correlation between oncogenic GNAQQ209P mutation and sustained ERK1/2-MAPK activation, implying that ERK1/2 signalling is unlikely to be instrumental in the maintenance of GNAQQ209P-driven UMs.

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Section: Discussionmentioning

confidence: 99%

Minimal contribution of ERK1/2-MAPK signalling towards the maintenance of oncogenic GNAQQ209P-driven uveal melanomas in zebrafish

et al. 2016

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“…These mice develop melanomas, in the hairless skin of ear, tail, and anus, and also develop choroidal hyperplastic lesions and UM-like tumors. Furthermore, GRM1 is expressed in human uveal and skin melanoma, suggesting that the glutamate signaling pathway is a possible target for UM therapy [399]. …”

Section: Animal Modelsmentioning

confidence: 99%

The biology of uveal melanoma

Amaro

Gangemi

Piaggio

et al. 2017

Cancer Metastasis Rev

192

193

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Uveal melanoma (UM), a rare cancer of the eye, is distinct from cutaneous melanoma by its etiology, the mutation frequency and profile, and its clinical behavior including resistance to targeted therapy and immune checkpoint blockers. Primary disease is efficiently controlled by surgery or radiation therapy, but about half of UMs develop distant metastasis mostly to the liver. Survival of patients with metastasis is below 1 year and has not improved in decades. Recent years have brought a deep understanding of UM biology characterized by initiating mutations in the G proteins GNAQ and GNA11. Cytogenetic alterations, in particular monosomy of chromosome 3 and amplification of the long arm of chromosome 8, and mutation of the BRCA1-associated protein 1, BAP1, a tumor suppressor gene, or the splicing factor SF3B1 determine UM metastasis. Cytogenetic and molecular profiling allow for a very precise prognostication that is still not matched by efficacious adjuvant therapies. G protein signaling has been shown to activate the YAP/TAZ pathway independent of HIPPO, and conventional signaling via the mitogen-activated kinase pathway probably also contributes to UM development and progression. Several lines of evidence indicate that inflammation and macrophages play a pro-tumor role in UM and in its hepatic metastases. UM cells benefit from the immune privilege in the eye and may adopt several mechanisms involved in this privilege for tumor escape that act even after leaving the niche. Here, we review the current knowledge of the biology of UM and discuss recent approaches to UM treatment.

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“…Analysis of human melanoma cell lines and biopsies showed that 40% were positive for GRM1 expression, whereas in normal primary melanocytes expression was undetectable [96]. GRM1 expression has also been shown in uveal melanomas, and this association has been validated by the susceptibility of the Dct-Grm1 transgenic mice to uveal melanocytic neoplasia [97]. …”

Section: Melanoma Mouse Modelsmentioning

confidence: 99%

Genetically engineered mouse models of melanoma

Pérez-Guijarro

Day

Merlino

et al. 2017

Cancer

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Melanoma is a complex disease that exhibits highly heterogeneous etiological, histopathological, and genetic features, as well as therapeutic responses. Genetically engineered mouse (GEM) models provide powerful tools to unravel the molecular mechanisms critical for melanoma development and drug resistance. Here we expound briefly the basis of the mouse modeling design, the available technology for genetic engineering, and the aspects influencing the use of GEMs to model melanoma. Furthermore, we describe in detail the currently available GEM models of melanoma.

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Tg(Grm1) transgenic mice: A murine model that mimics spontaneous uveal melanoma in humans?

Cited by 35 publications

References 30 publications

Minimal contribution of ERK1/2-MAPK signalling towards the maintenance of oncogenic GNAQQ209P-driven uveal melanomas in zebrafish

Minimal contribution of ERK1/2-MAPK signalling towards the maintenance of oncogenic GNAQQ209P-driven uveal melanomas in zebrafish

The biology of uveal melanoma

Genetically engineered mouse models of melanoma

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