Human embryonic stem cell-derived neural crest model unveils CD55 as a cancer stem cell regulator for therapeutic targeting in MYCN-amplified neuroblastoma
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AbstractBackground
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 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 non-canonical 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 novel 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.
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 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 non-canonical 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 novel 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.
Acceptance Date16/10/2021
All Author(s) ListZhihui Weng, Jiacheng Lin, Jiaozi He, Lin Gao, Sien Lin, Lai Ling Tsang, Hang Zhang, Xiaoyan He, Guang Wang, Xuesong Yang, Hu Zhou, Hui Zhao, Gang Li, Lin Zou, Xiaohua Jiang
Journal nameNeuro-Oncology
Year2022
Month6
Day1
Volume Number24
Issue Number6
PublisherOxford University Press
Pages872 - 885
ISSN1522-8517
eISSN1523-5866
LanguagesEnglish-United Kingdom
Keywordsneuroblastoma, disease model, human embryonic stem cells, MYCN, CD55
