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Bone marrow stromal cells dictate lanosterol biosynthesis and ferroptosis of multiple myeloma

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机构： [1]Department of Pathology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China [2]Central Laboratory,Linyi People’s Hospital, Linyi, Shandong Province 276037, China [3]Department of Hematology, The First People’s Hospital of Chuzhou, Chuzhou Hospital Affiliated to AnhuiMedical University, Chuzhou 239000, China [4]Department of Hematology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, Jiangsu 210008, China [5]The Province andMinistry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases, School of Basic MedicalScience, Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin 300070, China [6]School of Stomatology,Tianjin Medical University, Heping, Tianjin 300070, China [7]Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin KeyLaboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin 300192, China [8]School of Natual Science, University of Texas at Austin, Austin,TX 78712, USA [9]Division of Nephrology and Hypertension, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA [10]Division of Hematology/Oncology, Mayo Clinic Arizona, Scottsdale,AZ 85259, USA [11]The Proton Center of Shandong Cancer Institute and Hospital, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong250117, China

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Ferroptosis has been demonstrated a promising way to counteract chemoresistance of multiple myeloma (MM), however, roles and mechanism of bone marrow stromal cells (BMSCs) in regulating ferroptosis of MM cells remain elusive. Here, we uncovered that MM cells were more susceptible to ferroptotic induction under the interaction of BMSCs using in vitro and in vivo models. Mechanistically, BMSCs elevated the iron level in MM cells, thereby activating the steroid biosynthesis pathway, especially the production of lanosterol, a major source of reactive oxygen species (ROS) in MM cells. We discovered that direct coupling of CD40 ligand and CD40 receptor constituted the key signaling pathway governing lanosterol biosynthesis, and disruption of CD40/CD40L interaction using an anti-CD40 neutralizing antibody or conditional depletion of Cd40l in BMSCs successfully eliminated the iron level and lanosterol production of MM cells localized in the Vk*MYC Vk12653 or NSG mouse models. Our study deciphers the mechanism of BMSCs dictating ferroptosis of MM cells and highlights the therapeutic potential of non-apoptosis strategies for managing refractory or relapsed MM patients.© 2024. The Author(s).

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大类 | 1 区

医学

小类 | 1 区生化与分子生物学 1 区遗传学 2 区细胞生物学 2 区肿瘤学

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Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 CELL BIOLOGY Q1 GENETICS & HEREDITY Q1 ONCOLOGY

影响因子： 6.9 最新[2023版] 7.5 最新五年平均 6.9 出版当年[2023版] 0 出版当年五年平均 6.9 出版前一年[2023版]

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第一作者机构： [1]Department of Pathology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China

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