The neural crest origin of uveal melanomas

Arnesen, K

doi:10.1007/bf00128360

Cited by 9 publications

(8 citation statements)

References 23 publications

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“…Once metastasized, there is no effective therapy with an average survival of 2–8 months (Singh et al, 2005). Unlike cutaneous melanoma, UM originates from melanocytes of the choroid, ciliary body, and iris (collectively known as the uvea) derived from the neural crest (Arnesen, 1985). Molecular genetic analyses show that the mutational spectrum of UM is very different from cutaneous melanoma.…”

Section: Introductionmentioning

confidence: 99%

Mutant Gq/11 Promote Uveal Melanoma Tumorigenesis by Activating YAP

et al. 2014

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SUMMARY Uveal melanoma (UM) is the most common cancer in adult eyes. Approximately eighty percent of UMs harbor somatic activating mutations in GNAQ or GNA11 (encodes Gq or G11 respectively). Herein, we show in both cell culture and human tumors that cancer-associated Gq/11 mutants activate YAP, a major effector of the Hippo tumor suppressor pathway that is also regulated by G-protein coupled receptor (GPCR) signaling. YAP mediates the oncogenic activity of mutant Gq/11 in UM development, and the YAP inhibitor verteporfin blocks tumor growth of UM cells containing Gq/11 mutations. This study reveals an essential role of the Hippo-YAP pathway in Gq/11-induced tumorigenesis and suggests YAP as a potential drug target for UM patients carrying mutations in GNAQ or GNA11.

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Section: Introductionmentioning

confidence: 99%

Mutant Gq/11 Promote Uveal Melanoma Tumorigenesis by Activating YAP

et al. 2014

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“…Uveal melanoma (UM) originates from melanocytes within the uvea of the eye, a structure comprised of the choroidal plexus, ciliary body, or iris of the eye and represent the most common intraocular malignancy in adults ( 1 , 2 ). 50% of patients develop metastases, mainly to the liver (95% of patients) ( 1 ).…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of uveal melanoma oncogenes

Weng

Bastian

et al. 2020

Oncogene

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Uveal melanoma (UM) is a currently untreatable form of melanoma with a 50% mortality rate. Characterization of the essential signaling pathways driving this cancer is critical to develop target therapies. Activating mutations in the Gαq signaling pathway at the level of GNAQ, GNA11 or rarely CYSLTR2 or PLCβ4 are considered alterations driving proliferation in UM and several other neoplastic disorders. Here, we systematically examined the oncogenic signaling output of various mutations recurrently identified in human tumors. We demonstrate that CYSLTR2->GNAQ/11->PLCβ act in a linear signaling cascade that, via protein kinase C (PKC), activates in parallel the MAP-kinase and FAK/YAP pathways. Using genetic ablation and pharmacological inhibition, we show that the PKC/RasGRP3/MAPK signaling branch is the essential component that drives the proliferation of UM. Only inhibition of the MAPK branch but not the FAK branch synergizes with inhibition of the proximal cascade, providing a blueprint for combination therapy. All oncogenic signaling could be extinguished by the novel GNAQ/11 inhibitor YM-254890, in all UM cells with driver mutation in the Gαq subunit or the upstream receptor. Our findings highlight the GNAQ/11->PLCβ->PKC->MAPK pathway as the central signaling axis to be suppressed pharmacologically to treat for neoplastic disorders with Gαq pathway mutations.

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“…Uveal melanoma (UM) arises from melanocytes contained in the choroid, ciliary body, and iris (together known as the uvea) of the ocular cavity, and is the most common intraocular tumor in adults (1,2). UM accounts for approximately 5% of all lethal melanoma cases, and the current treatment options for eye localized disease are either surgery or radiation.…”

Section: Introductionmentioning

confidence: 99%

Effects of Oncogenic Gαq and Gα11 Inhibition by FR900359 in Uveal Melanoma

Lapadula

Farías

Randolph

et al. 2019

Molecular Cancer Research

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Uveal melanoma is the most common intraocular tumor in adults and often metastasizes to the liver, leaving patients with few options. Recurrent activating mutations in the G proteins, Gαq and Gα11, are observed in approximately 93% of all uveal melanomas. While therapeutic intervention of downstream Gαq/11 targets has been unsuccessful in treating uveal melanoma, using in vitro [35S]GTPγS binding and cell signaling assays we have found that the Gαq/11 inhibitor, FR900359 (FR), effectively inhibits oncogenic Gαq/11 signaling in uveal melanoma cells expressing either mutant Gαq or Gα11. Inhibition of oncogenic Gαq/11 by FR results in cell cycle arrest and induction of apoptosis. Furthermore, colony formation is prevented by FR treatment of uveal melanoma cells in 3D‐cell culture, providing promise for future in vivo studies. This suggests direct inhibition of activating Gαq/11 mutants may be a potential means of treating uveal melanoma. Support or Funding Information Dr. Ralph and Marian Falk Medical Research Trust and NIH award F31 CA225064 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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The neural crest origin of uveal melanomas

Cited by 9 publications

References 23 publications

Mutant Gq/11 Promote Uveal Melanoma Tumorigenesis by Activating YAP

Mutant Gq/11 Promote Uveal Melanoma Tumorigenesis by Activating YAP

Functional characterization of uveal melanoma oncogenes

Effects of Oncogenic Gαq and Gα11 Inhibition by FR900359 in Uveal Melanoma

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