posted on 2024-04-01, 07:23authored byYanyang Xu, Chuangzhong Deng, Hongmin Chen, YiJiang Song, Huaiyuan Xu, Guohui Song, Xinliang Wang, Tianqi Luo, Weiqing Chen, Jiahui Ma, Anyu Zeng, Shujing Huang, Zhihao Chen, Jianchang Fu, Ming Gong, Yi Tai, Anfei Huang, Huixiong Feng, Jinxin Hu, Xiaojun Zhu, Qinglian Tang, Jinchang Lu, Jin Wang
CXCL14 binds to heterodimeric integrin α11β1.
Funding
National Natural Science Foundation of China (NSFC)
Natural Science Foundation of Guangdong Province (廣東省自然科學基金)
History
ARTICLE ABSTRACT
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-naïve 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 α11β1 on fibroblasts activated actomyosin contractility and matrix remodeling properties. CXCL14-stimulated fibroblasts produced TGFβ and increased osteosarcoma invasion and migration. mAbs targeting the CXCL14-integrin α11β1 axis inhibited fibroblast TGFβ 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 α11β1 axis is a potential strategy to inhibit osteosarcoma lung metastasis.
Cooperation between stem-like osteosarcoma cells and fibroblasts mediated by a CXCL14-integrin α11β1 axis creates a tumor-supportive lung metastatic niche and represents a therapeutic target to suppress osteosarcoma metastasis.