High frequency of melanoma in cdkn2b-/- /tp53-/- Xenopus tropicalis.

Abstract

Rationale: Melanoma, the deadliest form of skin cancer characterized by high therapy resistance, has undergone extensive investigation through the utilization of BRAF^V600E-driven melanoma animal models. However, there exists a paucity of animal models for the rare hereditary melanoma resulting from germline CDKN2A mutations. Methods: Here, employing CRISPR/Cas9 technology, we generated cdkn2b^-/-/tp53^-/- Xenopus tropicalis on a tp53 knockout background to model human CDKN2A germline mutation-induced hereditary melanoma. Results: The findings unveiled that cdkn2b^-/-/tp53^-/- frogs spontaneously developed melanoma, pancreatic cancer, and other tumors. Specifically, these frogs exhibited a high penetrance of spontaneous melanoma, sharing characteristics with melanomas in human hereditary melanoma caused by germline CDKN2A mutations. During melanoma development in cdkn2b^-/-/tp53^-/- frogs, the occurrences of epithelial-to-mesenchymal transition, the reactivation of pigment cell progenitor cell transcriptional states, and the activation in the MAPK, NF-kB, PI3K-Akt, and TGF-β signaling pathways were noted. Conclusions: Overall, cdkn2b^-/-/tp53^-/- Xenopus tropicalis provides a vertebrate model for investigating the development of CDKN2A germline mutation-induced hereditary melanoma, contributing to the exploration of the pathogenesis of hereditary melanoma in humans.