2. Academic Validation
  3. FOXR2 Targets LHX6+/DLX+ Neural Lineages to Drive Central Nervous System Neuroblastoma

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

  • Cancer Res. 2025 Jan 15;85(2):231-250. doi: 10.1158/0008-5472.CAN-24-2248.
Selin Jessa # 1 2,  Antonella De Cola # 3 4,  Bhavyaa Chandarana # 1 5,  Michael McNicholas 3 4,  Steven Hébert 1,  Adam Ptack 6 7,  Damien Faury 7,  Jessica W Tsai 8 9 10,  Andrey Korshunov 11 12 13,  Timothy N Phoenix 14,  Benjamin Ellezam 15,  David T W Jones 16 17 18,  Michael D Taylor 19 20 21 22 23 24,  Pratiti Bandopadhayay 25 26 27 28,  Manav Pathania 3 4,  Nada Jabado 5 7 29,  Claudia L Kleinman 1 5
Affiliations

Affiliations

  • 1 Lady Davis Research Institute, Jewish General Hospital, Montreal, Canada.
  • 2 Quantitative Life Sciences, McGill University, Montreal, Canada.
  • 3 Department of Oncology, Early Cancer Institute, Adrian Way, University of Cambridge, Cambridge, United Kingdom.
  • 4 CRUK Children's Brain Tumour Centre of Excellence, University of Cambridge, Cambridge, United Kingdom.
  • 5 Department of Human Genetics, McGill University, Montreal, Canada.
  • 6 Department of Experimental Medicine, McGill University, Montreal, Canada.
  • 7 Research Institute of the McGill University Health Centre, Montreal, Canada.
  • 8 Department of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, California.
  • 9 Department of Pediatrics, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, California.
  • 10 The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California.
  • 11 Clinical Cooperation Unit Neuropathology (B300), German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), National Center for Tumor Diseases (NCT), Heidelberg, Germany.
  • 12 Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.
  • 13 Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg University Hospital and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 14 Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio.
  • 15 Department of Pathology, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Canada.
  • 16 Division of Pediatric Glioma Research, Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  • 17 National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany.
  • 18 German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 19 Pediatric Neuro-Oncology Research Program, Texas Children's Hospital, Houston, Texas.
  • 20 Department of Pediatrics, Hematology/Oncology, Hematology/Oncology Section, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas.
  • 21 Department of Neurosurgery, Baylor College of Medicine, Houston, Texas.
  • 22 Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Canada.
  • 23 Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Canada.
  • 24 The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
  • 25 Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • 26 Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
  • 27 Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 28 Boston Children's Cancer and Blood Disorder Center, Boston, Massachusetts.
  • 29 Department of Pediatrics, McGill University, Montreal, Canada.
  • # Contributed equally.
PMID: 39495206 DOI: 10.1158/0008-5472.CAN-24-2248
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.

Figures
Products