FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

作者全名："Zhou, Hong; Wang, Yan-Xia; Wu, Min; Lan, Xi; Xiang, Dongfang; Cai, Ruili; Ma, Qinghua; Miao, Jingya; Fang, Xuanyu; Wang, Junjie; Luo, Dan; He, Zhicheng; Cui, Youhong; Liang, Ping; Wang, Yan; Bian, Xiu-Wu"

作者地址："[Zhou, Hong; Bian, Xiu-Wu] Chongqing Univ, Sch Med, Chongqing, Peoples R China; [Zhou, Hong; Wang, Yan-Xia; Wu, Min; Lan, Xi; Xiang, Dongfang; Cai, Ruili; Ma, Qinghua; Miao, Jingya; Fang, Xuanyu; Wang, Junjie; Luo, Dan; He, Zhicheng; Cui, Youhong; Wang, Yan; Bian, Xiu-Wu] Army Med Univ, Third Mil Med Univ, Southwest Hosp, Inst Pathol, Chongqing, Peoples R China; [Zhou, Hong; Wang, Yan-Xia; Wu, Min; Lan, Xi; Xiang, Dongfang; Cai, Ruili; Ma, Qinghua; Miao, Jingya; Fang, Xuanyu; Wang, Junjie; Luo, Dan; He, Zhicheng; Cui, Youhong; Wang, Yan; Bian, Xiu-Wu] Army Med Univ, Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing, Peoples R China; [Zhou, Hong; Wang, Yan-Xia; Wu, Min; Lan, Xi; Xiang, Dongfang; Cai, Ruili; Ma, Qinghua; Miao, Jingya; Fang, Xuanyu; Wang, Junjie; Luo, Dan; He, Zhicheng; Cui, Youhong; Wang, Yan; Bian, Xiu-Wu] Key Lab Tumor Immunopathol, Chongqing, Peoples R China; [Wu, Min] Southern Med Univ, Sch Basic Med Sci, Dept Pathol, Guangzhou, Peoples R China; [Liang, Ping] Chongqing Med Univ, Childrens Hosp, Dept Neurosurg, Chongqing, Peoples R China; [Wang, Yan; Bian, Xiu-Wu] Inst Adv Pathol, Jinfeng Lab, Chongqing, Peoples R China; [Cui, Youhong; Wang, Yan; Bian, Xiu-Wu] Army Med Univ, Third Mil Med Univ, Southwest Hosp, Inst Pathol, Chongqing 400038, Peoples R China; [Cui, Youhong; Wang, Yan; Bian, Xiu-Wu] Army Med Univ, Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing 400038, Peoples R China; [Liang, Ping] Chongqing Med Univ, Childrens Hosp, Dept Neurosurg, Chongqing 400014, Peoples R China"

通信作者："Cui, YH; Wang, Y; Bian, XW (通讯作者)，Army Med Univ, Third Mil Med Univ, Southwest Hosp, Inst Pathol, Chongqing 400038, Peoples R China.; Cui, YH; Wang, Y; Bian, XW (通讯作者)，Army Med Univ, Third Mil Med Univ, Southwest Hosp, Southwest Canc Ctr, Chongqing 400038, Peoples R China.; Liang, P (通讯作者)，Chongqing Med Univ, Childrens Hosp, Dept Neurosurg, Chongqing 400014, Peoples R China."

来源：JOURNAL OF PATHOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001143949000001

JCR分区：Q1

影响因子：7.3

年份：2024

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：medulloblastoma; sonic hedgehog; FANCD2; ferroptosis; radiotherapy; single-cell transcriptomics

摘要："Radiotherapy is one of the standard therapeutic regimens for medulloblastoma (MB). Tumor cells utilize DNA damage repair (DDR) mechanisms to survive and develop resistance during radiotherapy. It has been found that targeting DDR sensitizes tumor cells to radiotherapy in several types of cancer, but whether and how DDR pathways are involved in the MB radiotherapy response remain to be determined. Single-cell RNA sequencing was carried out on 38 MB tissues, followed by expression enrichment assays. Fanconi anemia group D2 gene (FANCD2) expression was evaluated in MB samples and public MB databases. The function of FANCD2 in MB cells was examined using cell counting assays (CCK-8), clone formation, lactate dehydrogenase activity, and in mouse orthotopic models. The FANCD2-related signaling pathway was investigated using assays of peroxidation, a malondialdehyde assay, a reduced glutathione assay, and using FerroOrange to assess intracellular iron ions (Fe2+). Here, we report that FANCD2 was highly expressed in the malignant sonic hedgehog (SHH) MB subtype (SHH-MB). FANCD2 played an oncogenic role and predicted worse prognosis in SHH-MB patients. Moreover, FANCD2 knockdown markedly suppressed viability, mobility, and growth of SHH-MB cells and sensitized SHH-MB cells to irradiation. Mechanistically, FANCD2 deficiency led to an accumulation of Fe2+ due to increased divalent metal transporter 1 expression and impaired glutathione peroxidase 4 activity, which further activated ferroptosis and reduced proliferation of SHH-MB cells. Using an orthotopic mouse model, we observed that radiotherapy combined with silencing FANCD2 significantly inhibited the growth of SHH-MB cell-derived tumors in vivo. Our study revealed FANCD2 as a potential therapeutic target in SHH-MB and silencing FANCD2 could sensitize SHH-MB cells to radiotherapy via inducing ferroptosis. (c) 2024 The Pathological Society of Great Britain and Ireland."

基金机构："Chongqing Scientific and Technological Commission [31991172, 81821003, 82192890, X-WB, 81972365]; National Science Foundation of China [2023CCXM001 to X-WB]; Joint Project of Chongqing Scientific and Technological Commission [cstc2020jcyj-msxmX0375, 2023NSCQ-MSX4276, 2022YSZX-JCX0006CSTB]; Natural Science Foundation Project of Chongqing [2019XQY08]; Frontier Exploration Project of Army Medical University"

基金资助正文："We thank Dr Haibo Wu in The First Affiliated Hospital of University of Science and Technology of China for the specimen collection. We thank Cong Chen, Rong Zhou, and Hui-Min Lu of Southwest Hospital Biobank for their help with the follow-up of patients. This study was supported by the National Science Foundation of China (31991172, 81821003, and 82192890 to X-WB; 81972365 to YW), the Joint Project of Chongqing Scientific and Technological Commission (2023CCXM001 to X-WB), the Natural Science Foundation Project of Chongqing (cstc2020jcyj-msxmX0375 to DFX, 2023NSCQ-MSX4276 to YW, and 2022YSZX-JCX0006CSTB to ZCH), the Frontier Exploration Project of Army Medical University (2019XQY08 to YW)."