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Human Retinal Organoid Modeling Defines Developmental Window and Therapeutic Vulnerabilities in MYCN-Amplified
Jinkyu Park1, Gang Cui1, Jiyun Hong2
1Department of Ophthalmology, Severance Eye Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
International Journal of Molecular Sciences
|September 13, 2025
Summary
MYCN amplification drives a rare, aggressive retinoblastoma subtype. Researchers used human retinal organoids to identify a developmental window for tumor formation and found that transcriptional inhibitors are a promising therapy for this pediatric cancer.
Area of Science:
- Developmental biology
- Cancer research
- Genetics
Background:
- MYCN amplification without RB1 mutations defines an aggressive retinoblastoma subtype.
- The developmental origins and therapeutic vulnerabilities of this subtype are poorly understood.
Purpose of the Study:
- To model MYCN-amplified retinoblastoma using human pluripotent stem cell-derived retinal organoids.
- To identify the developmental window of susceptibility to transformation.
- To uncover therapeutic vulnerabilities specific to this subtype.
Main Methods:
- Lentiviral-mediated MYCN overexpression in human retinal organoids.
- Xenografting of MYCN-overexpressing organoids into immunodeficient mice.
- Transcriptomic profiling and pharmacological screening.
Main Results:
- A critical developmental window (days 70-120) for retinal progenitor transformation was identified.
- MYCN-overexpressing organoids recapitulated molecular features of patient tumors, activating MYC/E2F and mTORC1 pathways.
- MYCN-driven retinoblastoma cells showed specific sensitivity to transcriptional inhibitors (THZ1, Flavopiridol) and Volasertib.
Conclusions:
- This study elucidates the developmental and molecular basis of MYCN-driven retinoblastoma.
- A robust human retinal organoid platform for studying this cancer was established.
- Targeted transcriptional inhibition presents a promising therapeutic strategy for this aggressive pediatric cancer.
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