FOXR2 targets LHX6+/DLX+ neural lineages to drive central nervous system neuroblastoma

• Verfasst von: Jessa, Selin [VerfasserIn]
• Verfasst von: De Cola, Antonella [VerfasserIn]
• Verfasst von: Chandarana, Bhavyaa [VerfasserIn]
• Verfasst von: McNicholas, Michael [VerfasserIn]
• Verfasst von: Hébert, Steven [VerfasserIn]
• Verfasst von: Ptack, Adam [VerfasserIn]
• Verfasst von: Faury, Damien [VerfasserIn]
• Verfasst von: Tsai, Jessica W. [VerfasserIn]
• Verfasst von: Korshunov, Andrey [VerfasserIn]
• Verfasst von: Phoenix, Timothy N. [VerfasserIn]
• Verfasst von: Ellezam, Benjamin [VerfasserIn]
• Verfasst von: Jones, David T. W. [VerfasserIn]
• Verfasst von: Taylor, Michael D. [VerfasserIn]
• Verfasst von: Bandopadhayay, Pratiti [VerfasserIn]
• Verfasst von: Pathania, Manav [VerfasserIn]
• Verfasst von: Jabado, Nada [VerfasserIn]
• Verfasst von: Kleinman, Claudia L. [VerfasserIn]
• Titel: FOXR2 targets LHX6+/DLX+ neural lineages to drive central nervous system neuroblastoma
• Verf.angabe: Selin Jessa, Antonella De Cola, Bhavyaa Chandarana, Michael McNicholas, Steven Hébert, Adam Ptack, Damien Faury, Jessica W. Tsai, Andrey Korshunov, Timothy N. Phoenix, Benjamin Ellezam, David T.W. Jones, Michael D. Taylor, Pratiti Bandopadhayay, Manav Pathania, Nada Jabado, and Claudia L. Kleinman
• E-Jahr: 2025
• Jahr: November 4, 2024
• Umfang: 20 S.
• Fussnoten: Gesehen am 17.07.2025
• Titel Quelle: Enthalten in: Cancer research
• Ort Quelle: Philadelphia, Pa. : AACR, 1941
• Jahr Quelle: 2025
• Band/Heft Quelle: 85(2025), 2, Seite 231-250
• ISSN Quelle: 1538-7445
• DOI: doi:10.1158/0008-5472.CAN-24-2248
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1931021953

Abstract

Central nervous system neuroblastoma with forkhead box R2 (FOXR2) activation (NB-FOXR2) is a high-grade tumor of the brain hemispheres and a newly identified molecular entity. Tumors express dual neuronal and glial markers, leading to frequent misdiagnoses, and limited information exists on the role of FOXR2 in their genesis. To identify their cellular origins, we profiled the transcriptomes of NB-FOXR2 tumors at the bulk and single-cell levels and integrated these profiles with large single-cell references of the normal brain. NB-FOXR2 tumors mapped to LHX6+/DLX+ lineages derived from the medial ganglionic eminence, a progenitor domain in the ventral telencephalon. In vivo prenatal Foxr2 targeting to the ganglionic eminences in mice induced postnatal cortical tumors recapitulating human NB-FOXR2-specific molecular signatures. Profiling of FOXR2 binding on chromatin in murine models revealed an association with ETS transcriptional networks, as well as direct binding of FOXR2 at key transcription factors that coordinate initiation of gliogenesis. These data indicate that NB-FOXR2 tumors originate from LHX6+/DLX+ interneuron lineages, a lineage of origin distinct from that of other FOXR2-driven brain tumors, highlight the susceptibility of ventral telencephalon-derived interneurons to FOXR2-driven oncogenesis, and suggest that FOXR2-induced activation of glial programs may explain the mixed neuronal and oligodendroglial features in these tumors. More broadly, this work underscores systematic profiling of brain development as an efficient approach to orient oncogenic targeting for in vivo modeling, critical for the study of rare tumors and development of therapeutics.Significance: Profiling the developing brain enabled rationally guided modeling of FOXR2-activated CNS neuroblastoma, providing a strategy to overcome the heterogeneous origins of pediatric brain tumors that hamper tumor modeling and therapy development.See related commentary by Orr, p. 195