Osteosarcoma Cells Secrete CXCL14 That Activates Integrin 111 on Fibroblasts to Form a Lung Metastatic Niche

Cooperation between primary malignant cells and stromal cells can mediate the establishment of lung metastatic niches. Here, we characterized the landscape of cell populations in the tumor microenvironment in treatment-naive osteosarcoma using single-cell RNA sequencing and identified a stem cell-like cluster with tumor cell-initiating properties and prometastatic traits. CXCL14 was specifically enriched in the stem cell-like cluster and was also significantly upregulated in lung metastases compared with primary tumors. CXCL14 induced stromal reprogramming and evoked a malignant phenotype in fibroblasts to form a supportive lung metastatic niche. Binding of CXCL14 to heterodimeric integrin alpha 11 beta 1 on fibroblasts activated actomyosin contractility and matrix remodeling properties. CXCL14-stimulated fibroblasts produced TGF beta and increased osteosarcoma invasion and migration. mAbs targeting the CXCL14-integrin alpha 11 beta 1 axis inhibited fibroblast TGF beta production, enhanced CD8(+) T cell-mediated antitumor immunity, and suppressed osteosarcoma lung metastasis. Taken together, these findings identify cross-talk between osteosarcoma cells and fibroblasts that promotes metastasis and demonstrate that targeting the CXCL14-integrin alpha 11 beta 1 axis is a potential strategy to inhibit osteosarcoma lung metastasis. Significance: Cooperation between stem-like osteosarcoma cells and fibroblasts mediated by a CXCL14-integrin alpha 11 beta 1 axis creates a tumor-supportive lung metastatic niche and represents a therapeutic target to suppress osteosarcoma metastasis.