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 patients with osteosarcoma 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 the metastatic colonization of circulating tumor cells to the lung is needed to develop biologically defined, metastasis-targeting therapies. In this study, 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 hypoproliferative cells with the unique capacity to sustain the 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. Significance: Elucidation of key traits of metastasis-competent cancer cells identified cross-talk between osteosarcoma and lung epithelial cells that mediates metastasis and revealed IL1 inhibition as a promising therapeutic strategy for blocking metastasis.