TY - JOUR
T1 - Bone marrow stromal cells dictate lanosterol biosynthesis and ferroptosis of multiple myeloma
AU - Jiang, Hongmei
AU - Wang, Lijuan
AU - Zhang, Qiguo
AU - Wang, Sheng
AU - Jia, Linchuang
AU - Cheng, Hao
AU - Wang, Jingya
AU - Li, Xin
AU - Xie, Ying
AU - Wang, Yixuan
AU - Hu, Meilin
AU - Guo, Jing
AU - Li, Qian
AU - Peng, Ziyi
AU - Wang, Mengqi
AU - Xie, Yangyang
AU - Li, Tiantian
AU - Wang, Yafei
AU - Geng, Bill D.
AU - Swaminathan, Sundararaman
AU - Bergsagel, P. Leif
AU - Liu, Zhiqiang
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024
Y1 - 2024
N2 - 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. (Figure presented.)
AB - 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. (Figure presented.)
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U2 - 10.1038/s41388-024-03020-5
DO - 10.1038/s41388-024-03020-5
M3 - Article
AN - SCOPUS:85189883986
SN - 0950-9232
JO - Oncogene
JF - Oncogene
ER -