Let's talk about sex… obesity and melanoma

Abstract

The World Health Organization (WHO) has recently reported that more than 39% of adults are currently overweight or obese, globally, raising concerns for the prevalence of obesity-related conditions, such as certain cancers, including melanoma. Moreover, the WHO estimated that the global number of cases of melanoma – the most lethal skin cancer – are due to increase by more than 50% between 2020 and 2040. Despite this, the link between obesity and melanoma remains unclear, although some human studies have reported sex-dependent effects that impact this association.To examine this further, Emily Montal and colleagues in Richard White's lab investigated the effect of genetic- and diet-induced obesity, as well as sex, on melanoma initiation and progression in zebrafish. The authors overexpressed AgRP – a neuropeptide that regulates food intake – in embryonic zebrafish. AgRP overexpression increased several clinical signs of obesity when the fish reached adulthood and augmented these obesogenic effects in response to a high fat diet (HFD). Interestingly, males and females showed differences in these clinical signs of obesity. These zebrafish also harboured a mutated BRAF oncogene in the embryonic melanocytes to allow initiation of melanoma later in life. Montal and colleagues examined melanoma onset and progression by imaging the optically transparent casper zebrafish to assess hyperpigmentation and lesion growth, and found that obese male zebrafish overexpressing AgRP developed melanoma tumours significantly faster than their lean counterparts; however, this was not observed in females. The team then used a more-precise approach to induce melanoma by specifically activating BRAF in adult zebrafish skin cells. They found that, in male zebrafish, AgRP overexpression and HFD, alone or combined, enhanced tumour initiation and, to a lesser extent, tumour progression. However, in female zebrafish, enhanced tumour initiation was only detected when AgRP overexpression and HFD were combined, and no effect was observed on tumour progression at later stages.In their article, White and colleagues present the first account of melanoma initiation dependent on sex as well as obesity in an animal model, which crucially mirrors findings on sex differences in human studies. With rising prevalence of obesity and melanoma worldwide, this study sets the stage to delineate the mechanism underlying these important interactions. Furthermore, with historic sex-bias in scientific research causing disparity in patient treatment, studies that unravel sex-dependent mechanisms of disease are of utmost importance.