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Modeling the effects of genetic and diet induced obesity on melanoma progression in zebrafish

Obesity is a rising concern and associated with an increase in numerous cancers often in a sex-specific manner. Preclinical models are needed to deconvolute the intersection between obesity, sex, and cancer. We have generated a zebrafish system that can be used as a platform for studying these factors. We studied how germline overexpression of AgRP along with a high-fat diet (HFD) affects melanomas dependent on BRAFV600E. This revealed an increase in tumor incidence and area in male obese fish, but not females, consistent with the clinical literature. This is dependent on the somatic mutations, as male tumors generated with an RB1 mutation are sensitive to obesity, but this is not observed with PTEN. These data indicate that both germline and somatic mutations contribute to obesity related effects in melanoma. Given the rapid genetic tools available in the zebrafish, this provides a high-throughput system to dissect the interactions of genetics, diet, sex, and host factors in obesity-related cancers. Summary Statement Due to the rising incidence of obesity, there is a corresponding increased occurrence of obesity related cancers, which is often described to be dependent on sex. Here we developed a model to investigate the intersection between obesity, sex, and cancer.