Heterospecific developmental models highlight the role ofFBXO32in neural crest lineages and the significance of its variant in pediatric melanoma

Author:

Alexandra Vargas,Clémence Guillermain,Tatiana Gorojankina,Sophie Creuzet

Abstract

ABSTRACTMelanoma is a rare sporadic pediatric cancer caused byde novogenetic accidents. To analyze the involvement ofFBXO32of unknown biological significance, we set up original developmental invivo,ex vivo, andin vitromodels to unmask the biological role ofFBXO32in cephalic and trunk neural crest lineages. We show thatFBXO32silencing impairs melanocyte proliferation, differentiation, and vascularization. In rescue experiments, co-electroporation with the human wild-type gene compensates for the silencing of the endogenous gene and restores normal melanocyte phenotypes. By contrast, co-electroporation with the human variant,FBXO32G139S, alters melanocyte differentiation, pigment synthesis, triggers migration to the dermis, and favors angiotropism. Transcriptomic analysis reveals targets associated with melanocyte transformation, cytoskeleton remodeling, and focal adhesion. We show thatFBXO32orchestrates unexpected interactions withASIPfor melanogenesis andBAP1for the post-translational ubiquitination system. We proposeFBXO32as a tumor suppressor gene capable of preventing the onset of pediatric melanoma.

Publisher

Cold Spring Harbor Laboratory

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