Stromal Changes In The Aged Lung Induce An Emergence From Melanoma Dormancy

Dormant tumor cells escape the primary site, do not grow out into macroscopic tumors in the distal site, but maintain enough plasticity to reactivate and form overt metastatic lesions, sometimes taking several decades. Despite its importance in metastasis and residual disease, few studies have been able to successfully model or characterize dormancy within melanoma. Here, we show that age-related changes in the lung microenvironment facilitate a permissive niche for efficient outgrowth of disseminated dormant tumor cells, in contrast to the aged skin, where age-related changes suppress melanoma growth but drive dissemination. A model of melanoma progression that addresses these microenvironmental complexities is the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state1–3. Dermal fibroblasts are key orchestrators of promoting phenotype switching in melanoma via changes in the secretion of soluble factors during aging4–8. Specifically, we have identified Wnt5A as a master regulator of activating metastatic dormancy, which enables efficient seeding and survival of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble Wnt antagonist sFRP1, which inhibits Wnt5A, enabling efficient metastatic outgrowth. Further, we have identified the tyrosine kinase receptors AXL and MER as promoting a dormancy-to-reactivation axis respectively. Overall, we find that age-induced changes in distal metastatic microenvironments promotes efficient reactivation of dormant melanoma cells in the lung.