A tumor-associated photoreceptor signature unifies distinct central nervous system malignancies [bulkRNA-seq]

Pineoblastoma is a clinically aggressive childhood brain tumor that segregates into molecularly distinct subgroups. Mechanisms governing pineoblastoma pathogenesis, including developmental origins, remain poorly defined. Herein, we resolved the cellular composition of pineoblastoma and other pineal parenchymal tumors at single-cell resolution, aligning malignant cells with pineal gland development to retrace cellular origins. Integrative computational analyses mapped divergent pineoblastoma subgroups to cycling progenitors of the pinealocyte lineage. Lineage-specific perturbation of suspected drivers provoked the generation of genetically accurate preclinical models representing distinct molecular subgroups, while uncovering an oncogenic photoreceptor program conserved across pineoblastoma, retinoblastoma, and Group 3 medulloblastoma. Transcriptional activity of this program was acquired from cellular origin, incriminating photoreceptor identity as a common developmental vulnerability, substantiated as a strong dependency. Illuminated through multidisciplinary analysis of an uncommon, heterogeneous pediatric brain tumor, these advances motivate future studies evaluating developmentally encoded transcriptional programs of malignancy as potential therapeutic liabilities in clinically challenging entities.