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

CANCER RESEARCH(2024)

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摘要
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.
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