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Bone-metastatic lung adenocarcinoma cells bearing CD74-ROS1 fusion interact with macrophages to promote their dissemination

Oncogene volume 43, pages 2215–2227 (2024)Cite this article

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Abstract

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.

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Fig. 1: In vivo selection of organ-specific metastatic subpopulations of LUAD cells.
Fig. 2: BoM cell subpopulations possess greater EMT plasticity and stemness than parental cells.
Fig. 3: CD74-ROS1 (C6; R34) fusion mutation is identified in BoM subpopulations and enhances EMT and invasion of LUAD cells.
Fig. 4: CCL5 mediates BoM cell-induced M2 polarization of macrophages.
Fig. 5: BoM-induced macrophages in turn promote EMT and invasion of LUAD cells via TGF-β/SMAD signaling.
Fig. 6: CD74-ROS1 activates STAT3 and thereby promotes the transcription of CCL5 in BoM cells.
Fig. 7: Targeting the CD74-ROS1/CCL5 axis impedes bone metastasis and secondary metastasis of BoM cells in vivo.

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Data availability

The RNA-seq data generated in Table S1 have been deposited in the Gene Expression Omnibus (GEO) database under the accession code GSE249364.

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Acknowledgements

We are grateful for the participation and cooperation from NSCLC patients. This work was supported in part by National Natural Science Foundation of China (82273372, 82073198), and Suzhou Key Laboratory for Molecular Cancer Genetics (SZS201209), and Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX22_3214, and KYCX23_3261), Collaborative Innovation Center of Molecular Medicine between Soochow University and Donghai County People’s Hospital (H230470), Clinical Medicine Research Institute of Soochow University and Suzhou BenQ Medical Center (H230467), and A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Author notes

  1. These authors contributed equally: Zhao Wang, Zhe Lei, Yong Wang, Shengjie Wang.

Authors and Affiliations

  1. Soochow University Laboratory of Cancer Molecular Genetics, Collaborative Innovation Center of Molecular Medicine between Soochow University and Donghai County People’s Hospital, Clinical Medicine Research Institute of Soochow University and Suzhou BenQ Medical Center, Suzhou Medical College of Soochow University, Suzhou, 215123, Jiangsu Province, China

    Zhao Wang, Zhe Lei, Yong Wang, Shengjie Wang, Jia-Ping Wang, Ersuo Jin, Xia Liu, Runfeng Sun & Hong-Tao Zhang

  2. Department of Genetics, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, 215123, Jiangsu Province, China

    Zhao Wang, Yong Wang, Ersuo Jin, Xia Liu & Hong-Tao Zhang

  3. Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou Medical College of Soochow University, Suzhou, 215006, Jiangsu Province, China

    Zhe Lei

  4. Department of Basic Medicine, Kangda College of Nanjing Medical University, Lianyungang, 222000, Jiangsu Province, China

    Shengjie Wang

  5. Donghai County People’s Hospital, Lianyungang, 222000, Jiangsu Province, China

    Jia-Ping Wang & Runfeng Sun

  6. Suzhou Key Laboratory for Molecular Cancer Genetics, Suzhou, 215123, Jiangsu Province, China

    Hong-Tao Zhang

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Contributions

ZW, RS, and H-TZ contributed to study concept and design. ZW, ZL, YW, and SW performed all the experiments. J-PW, EJ, and XL provided technical support. EJ, ZL, RS, and H-TZ analyzed the data, wrote the manuscript, and contributed to the interpretation of data and critical revision of the manuscript. H-TZ supervised the study.

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Correspondence to Runfeng Sun or Hong-Tao Zhang.

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Human NSCLC tissues were collected after informed consent was obtained from all patients. The study protocol was conducted in accordance with the Declaration of Helsinki and has been approved by the Ethics Committee of the First Affiliated Hospital of Soochow University.

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Wang, Z., Lei, Z., Wang, Y. et al. Bone-metastatic lung adenocarcinoma cells bearing CD74-ROS1 fusion interact with macrophages to promote their dissemination. Oncogene 43, 2215–2227 (2024). https://doi.org/10.1038/s41388-024-03072-7

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