Metastasis-Initiating Osteosarcoma Subpopulations Establish Paracrine Interactions with Lung and Tumor Cells to Create a Metastatic Niche

Abstract Osteosarcoma is an aggressive and deadly bone tumor, primarily afflicting children, adolescents, and young adults. Poor outcomes for osteosarcoma patients are intricately linked with the development of lung metastasis, which is responsible for nearly all deaths caused by osteosarcoma. Identification of the underlying cellular and molecular mechanisms that govern metastatic colonization of circulating tumor cells to the lung are needed to develop biologically defined, metastasis-targeting therapies. Herein, using a combination of an in vitro organotypic metastasis model, single-cell RNA sequencing, human xenograft models, and murine immunocompetent osteosarcoma models, we found that metastasis is initiated by a subpopulation of hypo-proliferative cells with the unique capacity to sustain production of metastasis promoting cytokines, such as IL6 and CXCL8, in response to lung epithelial cell derived IL1α. Critically, genomic and pharmacologic disruption of IL1 signaling in osteosarcoma cells significantly reduced metastatic progression. Collectively, this study shows that tumor-stromal interactions are important for metastasis and suggests that metastatic competency is driven in part by the ability of tumor cells to respond to cues from the metastatic niche. Disruption of tumor-stromal signaling is a promising therapeutic approach to interrupt metastasis progression.