BIRC5 drives cell-cycle dysregulation and represents a novel molecular target in retinoblastoma.
BIRC5 is selectively overexpressed in aggressive proliferating retinoblastoma tumor cells.
BIRC5 drives cell-cycle dysregulation and represents a novel molecular target in retinoblastoma.
Retinoblastoma is the most common pediatric intraocular malignancy, although it remains a rare disease overall, yet the molecular targets and therapeutic vulnerabilities sustaining its most aggressive proliferative cell states remain incompletely defined.
We aimed to identify actionable molecular regulators and potential therapeutic targets of malignant retinoblastoma progression using integrated single-cell transcriptomics and functional validation.
We analyzed single-cell RNA sequencing data from 189,431 cells derived from 13 retinoblastoma tumors and 3 normal fetal retina samples.
Clustering identified 10 retinal cell types, including cone precursor-like, cone-like, and two MKI67 + proliferative RB subpopulations enrichment of G2/M-phase genes and chromosomal instability pathways.
MKI67 + cells2 displayed hyperactivated cell cycle genes, chromosomal instability, and mitotic checkpoint dysregulation.
Functional assays demonstrated that BIRC5 overexpression promoted proliferation, invasion, migration, and CCND1/CDK4 activation, while suppressing CHEK2-p21-mediated checkpoint control.
Conversely, BIRC5 knockdown induced G1 cell cycle arrest and increased apoptotic activity, accompanied by activation of checkpoint pathways.
This study defines BIRC5 as a cell-state-specific regulator of malignant proliferation in retinoblastoma and provides a mechanistic rationale for targeting survivin in highly proliferative tumor subpopulations.