Related Experiment Video
Updated: Oct 19, 2025
Reconstruct Human Retinoblastoma In Vitro
Published on: October 11, 2022
A high-risk retinoblastoma subtype with stemness features, dedifferentiated cone states and neuronal/ganglion cell
Jing Liu1,2,3, Daniela Ottaviani1,2,4, Meriem Sefta1,2
1Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University, 75005, Paris, France.
Abstract:
Retinoblastoma is the most frequent intraocular malignancy in children, originating from a maturing cone precursor in the developing retina. Little is known on the molecular basis underlying the biological and clinical behavior of this cancer. Here, using multi-omics data, we demonstrate the existence of two retinoblastoma subtypes. Subtype 1, of earlier onset, includes most of the heritable forms. It harbors few genetic alterations other than the initiating RB1 inactivation and corresponds to differentiated tumors expressing mature cone markers. By contrast, subtype 2 tumors harbor frequent recurrent genetic alterations including MYCN-amplification. They express markers of less differentiated cone together with neuronal/ganglion cell markers with marked inter- and intra-tumor heterogeneity. The cone dedifferentiation in subtype 2 is associated with stemness features including low immune and interferon response, E2F and MYC/MYCN activation and a higher propensity for metastasis. The recognition of these two subtypes, one maintaining a cone-differentiated state, and the other, more aggressive, associated with cone dedifferentiation and expression of neuronal markers, opens up important biological and clinical perspectives for retinoblastomas.
Insights
Researchers identified two distinct retinoblastoma subtypes using multi-omics data. Subtype 1 is earlier onset and differentiated, while aggressive subtype 2 shows cone dedifferentiation and stemness features, impacting treatment strategies.
Area of Science:
- Ophthalmology
- Pediatric Oncology
- Molecular Biology
Background:
- Retinoblastoma is the most common childhood intraocular cancer.
- The molecular drivers of retinoblastoma's diverse clinical behaviors are poorly understood.
Purpose of the Study:
- To elucidate the molecular underpinnings of retinoblastoma heterogeneity.
- To identify distinct molecular subtypes of retinoblastoma.
Main Methods:
- Multi-omics data analysis was employed.
- Genetic alterations, gene expression profiles, and clinical data were integrated.
Main Results:
- Two retinoblastoma subtypes were identified: Subtype 1 (earlier onset, heritable forms, differentiated cone markers, few genetic alterations) and Subtype 2 (later onset, MYCN amplification, dedifferentiated cone/neuronal markers, stemness features, high heterogeneity).
- Subtype 2 exhibits stemness, low immune/interferon response, E2F/MYC/MYCN activation, and increased metastatic potential.
Conclusions:
- Distinct molecular subtypes of retinoblastoma exist, impacting tumor biology and clinical outcomes.
- Subtype 2 represents a more aggressive form associated with cone dedifferentiation and stemness, offering new therapeutic targets.
