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MECHANISMS OF RESISTANCE

Osteocyte-derived exosomes confer multiple myeloma resistance to chemotherapy through acquisition of cancer stem cell-like features

Leukemia volume 37, pages 1392–1396 (2023)Cite this article

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Multiple myeloma (MM), the second most common hematological malignancy, remains largely incurable, with most patients developing relapsed or refractory disease after treatment [1]. This clinical problem is thought to be caused by the bone marrow (BM) microenvironment, where MM cells reside and respond to treatment [2]. Understanding how MM cells escape treatment within the BM niche may be key to improving patient survival.

Osteocytes are the most abundant bone cell type within the BM, originating from the osteogenic differentiation of mesenchymal stem cells (MSCs) [3]. Osteocytes are linked to normal bone homeostasis and benign and malignant bone diseases through communication with other cells on the bone surface [3]. In MM, osteocytes are involved in tumor cell growth, homing to specific bone areas, tumor-induced bone destruction, and angiogenesis [4, 5], but how osteocytes impact MM therapeutic response is not fully known. Like other stromal cells, osteocytes release exosomes into the microenvironment [6, 7]. Exosomes are nanovesicles containing a wide range of miRNAs, mRNAs, and proteins. They play a crucial role in tumor development by mediating cellular communication between stroma and tumor [6, 7]. In this study, we explore the functional impact of osteocytes on MM therapeutic response and identify the signaling interplay between osteocytes and MM cells linked by osteocyte-derived exosomal miRNAs. We describe a novel mechanism of MM therapeutic resistance in the BM, which may provide a new strategy to prevent or treat MM by targeting the BM microenvironment.

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Fig. 1: Osteocyte-derived exosomes inhibit chemotherapy-induced tumor apoptosis and facilitate cancer stem cell-like features in MM cells.
Fig. 2: The exosomal miR-483-3p and miR-513a-5p mediate osteocyte exosome-induced MM cell stemness through regulation of HIF-1α protein stabilization.

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The authors declare that all data supporting the findings of this study are available within the article or its Supplementary Materials and from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the National Institutes of Health/National Cancer Institute (R01 awards CA190863 and CA193362), the American Cancer Society (Research Scholar Grant 127337-RSG-15-069-01-TBG), and the Cancer Prevention & Research Institute of Texas (RP220639). We thank the Myeloma Tissue Bank at Houston Methodist Research Institute. This work was also supported by the Research Pathology Core, Flow Cytometry Core, and Translational Imaging Core at Houston Methodist Research Institute. We thank Dr. Shaefali P. Rodgers, Houston Methodist Research Institute, who edited the manuscript; and Ms. Rachael E. Whitehead, Houston Methodist Research Institute, who did the illustration for Fig. 2K.

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  1. These authors contributed equally: Feifei Cheng, Zhiming Wang.

Authors and Affiliations

  1. Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA

    Feifei Cheng, Zhiming Wang, Gichun You, Jin He & Jing Yang

  2. Department of Chemistry, The University of Tokyo, Tokyo, Japan

    Yuhong Liu

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  1. Feifei Cheng
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Contributions

JY and FC designed the study and wrote the manuscript; FC, ZW, and GY performed the experiments; FC, ZW, YL, and JH analyzed the data and conducted the statistical analyses. All authors reviewed the final manuscript.

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Correspondence to Jing Yang.

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Cheng, F., Wang, Z., You, G. et al. Osteocyte-derived exosomes confer multiple myeloma resistance to chemotherapy through acquisition of cancer stem cell-like features. Leukemia 37, 1392–1396 (2023). https://doi.org/10.1038/s41375-023-01896-y

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