MassIVE MSV000088977

Partial Public PXD032025

Stromal Changes in The Aged Lung Induce an Emergence From Melanoma Dormancy

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Description

Disseminated cancer cells (DCCs) that escape the primary site can seed in distal tissues, but may take several years, or even decades to grow out into overt metastases, a phenomenon termed tumor dormancy. 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. We have previously shown that dermal fibroblasts are key orchestrators of promoting phenotype switching in primary melanoma tumors via changes in the secretion of soluble factors during aging4-8. Our new data identifies Wnt5A as a master regulator of activating melanoma DCC dormancy within the lung, which initially enables efficient dissemination and seeding 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-toreactivation axis respectively. Overall, we find that age-induced changes in distal metastatic microenvironments promotes efficient reactivation of dormant melanoma cells in the lung. [doi:10.25345/C5CZ32645] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: TMT10plex ; Melanoma ; Aged Lung

Contact

Principal Investigators:
(in alphabetical order) 		Ashani T. Weeraratna, Johns Hopkins Bloomberg School of Public Health, United States
Submitting User: tangh

Publications

Fane ME, Chhabra Y, Alicea GM, Maranto DA, Douglass SM, Webster MR, Rebecca VW, Marino GE, Almeida F, Ecker BL, Zabransky DJ, Hüser L, Beer T, Tang HY, Kossenkov A, Herlyn M, Speicher DW, Xu W, Xu X, Jaffee EM, Aguirre-Ghiso JA, Weeraratna AT.
Stromal changes in the aged lung induce an emergence from melanoma dormancy.
Nature. 2022 Jun;606(7913):396-405. Epub 2022 06 01.

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