Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Theranostics. 2022 Aug 1;12(13):5877-5887. doi: 10.7150/thno.73714. eCollection 2022.
Osteosarcoma (OS) is the most common primary bone tumor with a poor prognosis, but the detailed mechanism is still unclear. A comprehensive investigation of tumor microenvironment (TME) of OS might help find effective anti-tumor strategies. Single-cell transcriptomics is a powerful new tool to explore TME. Therefore, this study is designed to investigate the TME and gene expression pattern of primary and recurrent OS at the single-cell level. The single-cell RNA sequencing and bioinformatic analysis were conducted to investigate the cellular constitution of primary, recurrent, and lung metastatic OS lesions according to the datasets of GSE152048 and GSE162454. TIMER database was used to investigate the role of LOX in the prognosis of sarcoma. The functions of related cells and markers were further confirmed by and experiments. Cancer associated fibroblasts (CAFs) were found with a higher infiltrating level in recurrent OS, and were enriched in the epithelial-mesenchymal transition (EMT) pathway. CAFs showed remarkably increased expression of LOX, which might lead to EMT and poor prognosis of OS. Mechanically, LOX regulated the function of CAFs and macrophage polarization to remodel the tumor immune microenvironment. Moreover, LOX inhibitor could inhibit migration and promote apoptosis of OS both and . This study revealed the heterogeneity of recurrent OS and highlighted an innovative mechanism that CAFs regulate EMT of OS via LOX. Targeting LOX of CAFs showed promising efficacy in remodeling TME and treating recurrent OS.
骨肉瘤（OS）是预后较差的最常见原发性骨肿瘤，但其详细机制仍不清楚。全面研究骨肉瘤肿瘤微环境（TME）可能有助于找到有效的抗肿瘤策略。单细胞转录组学是探索 TME 的一种强大的新工具。因此，本研究旨在在单细胞水平上研究原发性和复发性骨肉瘤的 TME 和基因表达模式。根据 GSE152048 和 GSE162454 数据集，进行了单细胞 RNA 测序和生物信息学分析，以研究原发性、复发性和肺转移 OS 病变的细胞组成。通过 TIMER 数据库研究 LOX 在肉瘤预后中的作用。通过 和 实验进一步证实了相关细胞和标志物的功能。研究发现复发性骨肉瘤中存在更高浸润水平的癌症相关成纤维细胞（CAFs），并且富集在上皮-间充质转化（EMT）途径中。CAFs 表现出明显增加的 LOX 表达，这可能导致 EMT 和 OS 的不良预后。从机制上讲，LOX 调节 CAFs 和巨噬细胞极化的功能，以重塑肿瘤免疫微环境。此外，LOX 抑制剂能够抑制 OS 的迁移并促进凋亡，无论是 在体内还是体外。本研究揭示了复发性 OS 的异质性，并强调了 CAFs 通过 LOX 调节 OS 的 EMT 的创新机制。靶向 CAFs 的 LOX 显示出在重塑 TME 和治疗复发性 OS 方面有很大的疗效。
