Osteosarcoma cells exploit lung fibroblast-driven inflammatory microenvironment for metastasis formation

Abstract Metastatic colonization relies on the dynamic interaction between disseminated tumor cells and stromal cells in distant organs. Here, we investigate how osteosarcoma cells exploit this interplay with resident fibroblasts to establish a supportive niche for lung metastasis formation, which accounts for 90% of all metastatic sites in this malignancy.Lung fibroblasts were isolated from premetastatic osteosarcoma mouse models and profiled for activation status and fibrotic and inflammatory gene expression markers. Osteosarcoma cell response to paracrine fibroblast signaling regarding dormancy, stemness, therapy resistance, adhesion and metastatic ability was further evaluated. Lung metastasis formation, growth kinetics and survival outcomes were assessed in mouse models.Lung fibroblasts acquired an activated and alternative inflammatory phenotype in response to systemic signaling from osteosarcoma cells. Tumor cells adapt to this microenvironment by entering a transient dormant state and acquiring stemness features and resistance to doxorubicin. Moreover, fibroblast signaling increased osteosarcoma cell adhesion to fibronectin in an integrin β1-dependent manner. This phenotypic reprogramming of osteosarcoma cells accelerates lung metastasis formation in mice.In sum, primary osteosarcoma cells reshape and adapt to lung fibroblast-induced inflammatory environment for successful metastatic colonization, significantly impacting metastatic fate and outcome. Based on these findings, therapeutic strategies disrupting this dynamic interplay hold promise for preventing metastatic progression.