Abstract 3642: The aged lung promotes reactivation from metastatic melanoma dormancy

Abstract

Abstract Our previous data have indicated that while tumors grow more slowly in aged mouse skin, they form more lung metastases. We queried whether the lung microenvironment undergoes age-related changes that provide a permissive niche for metastatic outgrowth. Our data showed that secreted factors by lung fibroblasts changed during aging that promoted proliferation of melanoma cells via expression of the tyrosine kinase receptor MER. Further investigation of this MER-high phenotype revealed that these melanoma cells induce dramatic changes to the lung microenvironment via secretion of its primary ligand PROS1, which creates a more permissive niche for metastasis. It first acts in a paracrine manner to induce proliferation of previously dormant melanoma cells in the lung. MER induced secretion of PROS1 by melanoma cells also regulates the production of extracellular matrix (ECM) from lung fibroblasts. Specifically, healthy human lung fibroblasts produce thick, unified cellular derived matrices (CDMs) in vitro that are growth-restrictive to melanoma cells. Treatment of lung fibroblasts with conditioned media from MER-High melanoma cells or with recombinant-PROS1 alters CDM density and orientation, which resulted in a CDM that dramatically increased melanoma proliferation. Finally, we found that MER induced metastatic outgrowth of melanoma cells within the lungs of mice decreased CD4 and CD8 T-cells whilst increasing infiltration of and immunosuppressive T-regulatory cells (Tregs) and Myeloid Derived Suppressor Cells (MDSCs). Overall, we find that age-induced activation of melanoma cells towards a MER-high state within the lung can induce a cancer phenotype which dramatically alters fibroblast ECM production and immune cell infiltration to promote aggressive and efficient metastatic outgrowth and a growth permissive microenvironment for dormant melanoma cells. Citation Format: Mitchell Fane, Ashani Weeraratna. The aged lung promotes reactivation from metastatic melanoma dormancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3642.