大约 40% 的肺腺癌 (LUAD) 患者在病程中经常发生骨转移。然而，几乎没有建立任何 LUAD 骨转移的体内模型，导致人们对 LUAD 骨转移的机制了解甚少。在这里，我们通过向裸鼠左心室注射荧光素酶标记的LUAD细胞建立多器官转移模型，然后筛选出肺转移（LuM）和骨转移（BoM）细胞亚群。 BoM 细胞比 LuM 细胞表现出更强的干性和上皮间质转化 (EMT) 可塑性，最初在骨骼中定植，随后在重新注射到小鼠体内后传播到远处的器官。此外，在 BoM 细胞中检测到 CD74-ROS1 融合突变（C6；R34），但在 LuM 细胞中未检测到。从机制上讲，携带 CD74-ROS1 融合体的 BoM 细胞通过激活 STAT3 信号传导、在肿瘤微环境中招募巨噬细胞并强烈诱导巨噬细胞的 M2 极化，高度分泌 C-C 基序趋化因子配体 5 (CCL5) 蛋白。 BoM 细胞激活的巨噬细胞产生高水平的 TGF-β1，从而通过 TGF-β/SMAD2/3 信号传导促进 EMT 和 LUAD 细胞的侵袭。使用 Crizotinib（一种 ROS1 抑制剂）和 Maraviroc（一种 CCL5 受体抑制剂）在体内靶向 CD74-ROS1/CCL5 轴，可强烈阻碍 BoM 细胞的骨转移和继发性转移。我们的研究结果揭示了CD74-ROS1/STAT3/CCL5轴在LUAD骨转移细胞与巨噬细胞相互作用中控制LUAD细胞传播的关键作用，强调了骨微环境在LUAD骨转移和多器官继发转移中的重要性，并提示靶向 CD74-ROS1 和 CCL5 是一种有前途的 LUAD 骨转移治疗策略。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Approximately 40% of patients with lung adenocarcinoma (LUAD) often develop bone metastases during the course of their disease. However, scarcely any in vivo model of LUAD bone metastasis has been established, leading to a poor understanding of the mechanisms underlying LUAD bone metastasis. Here, we established a multiorgan metastasis model via the left ventricular injection of luciferase-labeled LUAD cells into nude mice and then screened out lung metastasis (LuM) and bone metastasis (BoM) cell subpopulations. BoM cells exhibited greater stemness and epithelial-mesenchymal transition (EMT) plasticity than LuM cells and initially colonized the bone and subsequently disseminated to distant organs after being reinjected into mice. Moreover, a CD74-ROS1 fusion mutation (C6; R34) was detected in BoM cells but not in LuM cells. Mechanistically, BoM cells bearing the CD74-ROS1 fusion highly secrete the C-C motif chemokine ligand 5 (CCL5) protein by activating STAT3 signaling, recruiting macrophages in tumor microenvironment and strongly inducing M2 polarization of macrophages. BoM cell-activated macrophages produce a high level of TGF-β1, thereby facilitating EMT and invasion of LUAD cells via TGF-β/SMAD2/3 signaling. Targeting the CD74-ROS1/CCL5 axis with Crizotinib (a ROS1 inhibitor) and Maraviroc (a CCL5 receptor inhibitor) in vivo strongly impeded bone metastasis and secondary metastasis of BoM cells. Our findings reveal the critical role of the CD74-ROS1/STAT3/CCL5 axis in the interaction between LUAD bone metastasis cells and macrophages for controlling LUAD cell dissemination, highlighting the significance of the bone microenvironment in LUAD bone metastasis and multiorgan secondary metastasis, and suggesting that targeting CD74-ROS1 and CCL5 is a promising therapeutic strategy for LUAD bone metastasis.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.