FOXR2 Targets LHX6+/DLX+ Neural Lineages to Drive Central Nervous System Neuroblastoma

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.

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Journal
Cancer Research
Published
2024-11-04
DOI
https://doi.org/10.1158/0008-5472.can-24-2248
Citations
1
Primary Topic
Neuroblastoma Research and Treatments
Type
article
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0.37
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article

FOXR2 Targets LHX6+/DLX+ Neural Lineages to Drive Central Nervous System Neuroblastoma

Claudia L. Kleinman, Damien Faury, Benjamin Ellezam, Michael McNicholas et al.
1 citations
Cancer Research
Neuroblastoma Research and Treatments
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article

FOXR2 Targets LHX6+/DLX+ Neural Lineages to Drive Central Nervous System Neuroblastoma

Claudia L. Kleinman, Damien Faury, Benjamin Ellezam, Michael McNicholas, Jessica W. Tsai, Antonella De Cola, Timothy N. Phoenix, Selin Jessa, Nada Jabado, Manav Pathania, Adam Ptack, Steven Hébert, Pratiti Bandopadhayay, Bhavyaa Chandarana, Michael D. Taylor, David Jones, Andrey Korshunov
article en
1 citations

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.

Cancer ResearchVol. 85(2)
Broad Institute (US), University of Southern California (US), Children's Hospital of Los Angeles (US), Harvard University (US), German Cancer Research Center (DE), Baylor College of Medicine (US), University of Toronto (CA), Heidelberg University (DE), University of Cambridge (GB), Montreal Children's Hospital (CA), Cancer Research UK (GB), Hospital for Sick Children (CA), McGill University Health Centre (CA), Jewish General Hospital (CA), University Hospital Heidelberg (DE), Centre Hospitalier Universitaire Sainte-Justine (CA), Cancer Research UK Cambridge Center (GB), Brain Tumour Research (GB), McGill-Queen's University Press (CA), National Center for Tumor Diseases (DE), Hopp Children's Cancer Center Heidelberg (DE), Dana-Farber Cancer Institute (US), McGill Genome Centre (CA), Texas Children's Hospital (US), Children's Cancer Center (US), Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US), McGill University (CA), University of Cincinnati (US), University of Cincinnati Medical Center (US)
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Neuroblastoma Research and Treatments
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