sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance

Aged fibroblasts release a Wnt antagonist, sFRP2, which drives a signalling cascade in melanoma cells, leading to increased metastasis and reduced effectiveness of targeted therapy. Age-related effects on cancer progression The incidence of cancer increases with age, leading Ashani Weeraratna and colleagues to consider the role that the ageing microenvironment plays in tumour progression. Here they report that aged fibroblasts release sFRP2 (secreted Frizzled-related protein 2), a modulator of the Wnt signalling pathway that drives a cascade leading to increased metastasis and reduced effectiveness of targeted therapy. These findings suggest the possibility of developing age-appropriate cancer treatments. Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression 1 , 2 , 3 , 4 , we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in β-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly.