English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

The heterotrimeric G protein α subunit oncogenes  GNAQ  or  GNA11  carry Q209X or R183X activating mutations and are present with ~90% frequency in human uveal melanomas. Forced expression of  GNAQ/11  Q209L  in melanocytes is sufficient to drive metastatic melanoma in immune-compromised mice. No known drugs directly target these oncogenic G proteins. Ric-8A is the molecular chaperone that selectively folds Gαq/i/13 subunits. Targeting Ric-8A serves as a rational, yet unexplored approach to reduce the functional abundance of oncogenic Gαq/11 in order to blunt cancer signaling. Here, using mouse melanocyte cell graft tumorigenesis models, we determined that  Ric-8A  genetic ablation attenuated the abundance and melanoma-driving potential of Gαq-Q209L. A new conditional  Ric-8A  Flox/Flox ;  Rosa-CreER  +/  −  mouse strain was derived and used as a tissue source to culture an immortalized, tamoxifen-inducible  Ric-8A  knockout melanocyte cell line that required 12- O -tetradecanoylphorbol-13-acetate (TPA, phorbol ester) for growth. The cell line failed to grow tumors when grafted into immune-compromised mice regardless of  Ric-8A  expression. Stable expression of human  GNAQ  Q209L , but not  GNAQ  WT  in the cell line promoted TPA-independent cell proliferation, and upon cell grafting in mice, the initiation and robust growth of darkly-pigmented melanoma tumors. Deletion of  Ric-8A  in  GNAQ  Q209L  cells restored TPA-dependent growth, reduced Gαq-Q209L below detectable levels and completely mitigated tumorigenesis from primary or secondary cell line grafts. Interestingly, TPA treatment of cultured  GNAQ  Q209L  cells or host animals grafted with  GNAQ  Q209L  cells also sharply reduced Gαq-Q209L abundance and tumorigenic capacity. Finally, tumorigenesis initiated from  GNAQ  Q209L  cell grafts, followed by host mouse systemic tamoxifen treatment to delete  Ric-8A  in the grafted cells completely abrogated  GNAQ  Q209L -driven tumor progression unless a stable human  RIC-8A  transgene was used to rescue the floxed  Ric-8A  alleles. Our work defines two new rational targets that may be developed as potential uveal melanoma therapies through reduction of Gαq/11-Q209L oncoprotein abundance: (1) Ric-8A inhibition and (2) phorbol ester treatment.

Ric-8A gene deletion or phorbol ester suppresses tumorigenesis in a mouse model of GNAQQ209L-driven melanoma