The Bateson-Dobzhansky-Muller (BDM) model describes negative epistatic interactions that occur between genes with a different evolutionary history to account for hybrid incompatibility and is a central theory explaining genetic mechanisms underlying speciation.,Since the early 1900 s when the BDM model was forwarded examples of BDM incompatibility have been described in only a few nonvertebrate cases.,This study reports the only vertebrate system, with clearly defined interacting loci, that supports the BDM model.,In addition, this study also poses that tumorigenesis serves as a novel mechanism that accounts for postzygotic isolation.,Mixing genomes of different species by hybridization can disrupt species-specific genetic interactions that were adapted and fixed within each species population.,Such disruption can predispose the hybrids to abnormalities and disease that decrease the overall fitness of the hybrids and is therefore named as hybrid incompatibility.,Interspecies hybridization between southern platyfish and green swordtails leads to lethal melanocyte tumorigenesis.,This occurs in hybrids with tumor incidence following progeny ratio that is consistent with two-locus interaction, suggesting melanoma development is a result of negative epistasis.,Such observations make Xiphophorus one of the only two vertebrate hybrid incompatibility examples in which interacting genes have been identified.,One of the two interacting loci has been characterized as a mutant epidermal growth factor receptor.,However, the other locus has not been identified despite over five decades of active research.,Here we report the localization of the melanoma regulatory locus to a single gene, rab3d, which shows all expected features of the long-sought oncogene interacting locus.,Our findings provide insights into the role of egfr regulation in regard to cancer etiology.,Finally, they provide a molecular explainable example of hybrid incompatibility.
Metastatic melanoma is challenging to manage.,Although targeted- and immune therapies have extended survival, most patients experience therapy resistance.,The adaptability of melanoma cells in nutrient- and therapeutically-challenged environments distinguishes melanoma as an ideal model for investigating therapy resistance.,In this review, we discuss the current available repertoire of melanoma models including two- and three-dimensional tissue cultures, organoids, genetically engineered mice and patient-derived xenograft.,In particular, we highlight how each system recapitulates different features of melanoma adaptability and can be used to better understand melanoma development, progression and therapy resistance.,Despite the new targeted and immunotherapies for metastatic melanoma, several patients show therapeutic plateau.,Here, the authors review the current pre-clinical models of cutaneous melanoma and discuss their strengths and limitations that may help with overcoming therapeutic plateau.