A tumor-associated photoreceptor signature unifies distinct central nervous system malignancies.
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Gudenas BL, Ahmad ST, Englinger B, Liu APY, Zhao M, Paul L, Hadley J, Li Y, Batts M, Mittal P, Wu SC, Lewis SA, Han K, Soliman T, Lin H, Janke L, Meredith D, Pfaff E, Gojo J, Cotter J, Klimo P, Boop FA, Gajjar A, Robinson GW, Rosén G, Alexandrescu S, Jones DTW, Orr BA, Swartling FJ, Filbin MG, Northcott PA
Cancer Cell 44 (4) 831-845.e10 [2026-04-13; online 2026-03-05]
Pineoblastoma is a clinically aggressive childhood brain tumor composed of distinct molecular subgroups with divergent driver genes, demographics, and clinical outcomes. To identify developmental origins and mechanisms governing disease pathogenesis, we derive single-cell transcriptomes from pineal parenchymal tumors, aligning malignant cells with developmental counterparts to retrace cellular origins. Integrative computational analyses map pineoblastoma origins to transient, cycling pinealocyte progenitors during development. Lineage-specific perturbation of suspected drivers in the early pineal gland yields preclinical models representative of consensus molecular subgroups. Multi-omic characterization of patient tumors and these models uncover a tumor-associated photoreceptor signature (TAPS) common to pineoblastoma, retinoblastoma, and Group 3 medulloblastoma. Transcriptional activity of this signature within respective cellular origins establishes a developmental basis for molecular similarities between entities. Photoreceptor signature constituents are selective dependencies across these anatomically distinct central nervous system malignancies, motivating future studies evaluating developmentally encoded programs of malignancy as potential therapeutic liabilities.
NGI Uppsala (SNP&SEQ Technology Platform) [Service]
National Genomics Infrastructure [Service]
PubMed 41791379
DOI 10.1016/j.ccell.2026.02.010
Crossref 10.1016/j.ccell.2026.02.010
mid: NIHMS2149981
pmc: PMC13123407
pii: S1535-6108(26)00108-X