Human embryonic stem cell-derived neural crest model unveils CD55 as a cancer stem cell regulator for therapeutic targeting in MYCN-amplified neuroblastoma

作者全名："Weng, Zhihui; Lin, Jiacheng; He, Jiaozi; Gao, Lin; Lin, Sien; Tsang, Lai Ling; Zhang, Hang; He, Xiaoyan; Wang, Guang; Yang, Xuesong; Zhou, Hu; Zhao, Hui; Li, Gang; Zou, Lin; Jiang, Xiaohua"

作者地址："[Weng, Zhihui; Lin, Jiacheng; Gao, Lin; Tsang, Lai Ling; Zhao, Hui; Jiang, Xiaohua] Chinese Univ Hong Kong, Key Lab Regenerat Med, Minist Educ China, Sch Biomed Sci,Fac Med, Hong Kong, Peoples R China; [Lin, Sien; Li, Gang] Chinese Univ Hong Kong, Fac Med, Dept Orthopaed & Traumatol, Hong Kong, Peoples R China; [Weng, Zhihui; Lin, Jiacheng; Gao, Lin; Lin, Sien; Tsang, Lai Ling; Zhao, Hui; Li, Gang; Jiang, Xiaohua] Chinese Univ Hong Kong, Shenzhen Res Inst, Shenzhen, Peoples R China; [Jiang, Xiaohua] Sichuan Univ, Sichuan Univ Chinese Univ Hong Kong Joint Lab Rep, West China Second Univ Hosp, Chengdu 610041, Peoples R China; [He, Jiaozi] Univ Hong Kong, Dept Clin Oncol, Fac Med, Hong Kong, Peoples R China; [Wang, Guang; Yang, Xuesong] Jinan Univ, Dept Histol & Embryol, Int Joint Lab Embryon Dev & Prenatal Med, Coll Med, Guangzhou 510632, Peoples R China; [Zhang, Hang; He, Xiaoyan; Zou, Lin] Chongqing Med Univ, Ctr Clin Mol Med, Childrens Hosp,Chongqing Int Sci & Technol Cooper, Minist Educ,Key Lab Child Dev & Disorders,Key Lab, Chongqing 400014, Peoples R China; [Zhou, Hu] Xiamen Univ, Sch Pharmaceut Sci, Fujian Prov Key Lab Innovat Drug Target Res, Xiamen 361102, Fujian, Peoples R China"

通信作者："Jiang, XH (通讯作者)，Chinese Univ Hong Kong, Key Lab Regenerat Med, Minist Educ China, Sch Biomed Sci,Fac Med, Hong Kong, Peoples R China.; Zou, L (通讯作者)，Chongqing Med Univ, Ctr Clin Mol Med, Childrens Hosp,Chongqing Int Sci & Technol Cooper, Minist Educ,Key Lab Child Dev & Disorders,Key Lab, Chongqing 400014, Peoples R China."

来源：NEURO-ONCOLOGY

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000805101500003

JCR分区：Q1

影响因子：15.9

年份：2022

卷号：24

期号：6

开始页：872

结束页：885

文献类型：Article

关键词：CD55; disease model; human embryonic stem cells; MYCN; neuroblastoma

摘要："Background Neuroblastoma (NB) is a common childhood malignant tumor of neural crest (NC) origin with remarkable heterogeneity in outcomes. Amplification of the oncogene MYCN is strongly associated with highly malignant behaviour and poor prognosis. Methods This study aims to use a human embryonic stem cell (hESC)-derived NC model to identify novel downstream effectors of MYCN that can be potentially used as prognostic marker and/or therapeutic target. Results We show that MYCN-driven NB derived from human neural crest cells (hNCCs) recapitulate the pathological and molecular features of MYCN-amplified neuroblastoma (MNA-NB). By using this platform, we identify a group of 14 surface protein-encoding genes that are associated with MYCN expression level in MNA-NB. Among these genes, high CD55 expression is correlated with poor survival in MNA-NB but not in non-MNA-NB. Furthermore, CD55 promotes tumorigenesis, tumor growth, and cancer stemness in MNA-NB cell lines (MNA-NBL) through regulating the JNK pathway. Mechanistically, MYCN binds to both canonical and noncanonical E-boxes on the promoter of CD55 to regulate its transcriptional expression. Finally, neutralizing antibody targeting CD55 significantly attenuates cancer stemness, suppresses tumor growth, and improves survival exclusively in MNA-NBL-inoculated mice. Conclusion MYCN shapes CD55 into a cancer stem cell regulator which represents a prognostic marker and therapeutic target of MNA-NB. The hESC-derived NC model serves as a valuable platform for investigating NB initiation and progression and developing potential therapeutic targets."

基金机构："University Grants Committee [GRF 14111519, 14165217, 466710]; Hong Kong Innovation and Technology Commission [ITS/448/18, MHP/024/19]; National Natural Science Foundation of China [NSFC 31970815, 31771517]; Guang Dong Province Science and Technology Grants [2018B030311065]"

基金资助正文："This work is supported by University Grants Committee (GRF 14111519, 14165217, 466710) and Hong Kong Innovation and Technology Commission (ITS/448/18, MHP/024/19). The work is also supported by National Natural Science Foundation of China (NSFC 31970815, 31771517) and Guang Dong Province Science and Technology Grants (2018B030311065)."