Melanoma is a disease of ageing, with elderly patients showing poorer prognosis than young patients. Across several epidemiological studies age and sex have emerged as the two independent factors underlying melanoma incidence, development, and survival. Overall, females have a significantly lower risk and better prognosis than males even when adjusted for age. While the role of aging microenvironment in melanoma progression is now recognized, the mechanisms underlying the sex disparity are not well understood. These differences have been attributed to inherent differences arising from sex chromosomes, gonadal hormones or host immune responses- these have been assessed on the tumor cells, but the role of the tumor surrounding dermal microenvironment is not well elucidated.
Dermal fibroblasts reside in close proximity to melanoma cells and have a profound impact on tumor progression. We examined if both sex-dependent and age-related changes in these fibroblasts can alter the course of melanoma tumor growth, metastasis and variable responses to targeted therapy. We found that dermal fibroblasts undergo age-mediated sex dimorphic changes in their proliferation, replicative senescence, and DNA damage response programs. In particular, aged male fibroblasts attain the multi-component senescence-associated secretory phenotype (SASP) earlier than age-matched females even though female fibroblast undergo early replicative senescence. We hypothesize that the slow rate of aging in female fibroblasts permits faster DNA repair as opposed to males where damage accrues with age. As a result, primary tumors in an aged male dermal microenvironment harbor elevated oxidative stress and grow slower than females. Primary tumors in the aged mice cohort are resistant to targeted BRAF/MEK inhibition. This is driven in part by bone morphogenetic protein-2 (BMP2) secreted specifically by the aged male dermal environment facilitating WNT5A and AXL expression and thus promoting a slow-cycling, invasive and therapy-resistant phenotype. Inhibition of BMP2 signaling in vitro and in the dermal microenvironment in vivo blocked the emergence of these slow-cycling phenotype and sensitized melanoma cells to BRAF/MEK inhibition. Overall, our studies demonstrate a molecular basis for the intersection of age and sex and provide some underlying mechanisms for the observed clinical disparity in the rates of melanoma in males and females.