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Cancer Cell. 2018 Mar 12;33(3):435-449.e6. doi: 10.1016/j.ccell.2018.02.006.

NRL and CRX Define Photoreceptor Identity and Reveal Subgroup-Specific Dependencies in Medulloblastoma.

Author information

1
Institut Curie - Recherche, Laboratoire 110, Centre Universitaire, Orsay Cedex 91405, France; INSERM U1021, Centre Universitaire, Orsay 91405, France; CNRS UMR 3347, Centre Universitaire, Orsay 91405, France; Université Paris Sud-11, 91405 Orsay, France; PSL Research University, Paris, France.
2
Baylor College of Medicine, Department of Molecular and Human Genetics, 1 Baylor Plaza, Houston, TX 77030, USA.
3
PSL Research University, Paris, France; Institut Curie, Paris 75248, France; INSERM U830, Paris 75248, France; Translational Research in Pediatric Oncology, Institut Curie SiRIC, Paris, France.
4
Institut Curie - Recherche, Laboratoire 110, Centre Universitaire, Orsay Cedex 91405, France; INSERM U1021, Centre Universitaire, Orsay 91405, France; CNRS UMR 3347, Centre Universitaire, Orsay 91405, France; Université Paris Sud-11, 91405 Orsay, France; PSL Research University, Paris, France; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS325, Memphis, TN 38017, USA.
5
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS325, Memphis, TN 38017, USA.
6
Departement de Neuropathologie, Hôpital Sainte-Anne, INSERM UMR_S1165, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
7
Institut Curie - Recherche, Laboratoire 110, Centre Universitaire, Orsay Cedex 91405, France.
8
Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Departement de Neuropathologie, Hôpital Sainte-Anne, INSERM U894, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
9
Institute of Neurology, Medical University of Vienna, Vienna, Austria.
10
Institut Curie - Recherche, Laboratoire 110, Centre Universitaire, Orsay Cedex 91405, France; Université Paris Sud-11, 91405 Orsay, France; PSL Research University, Paris, France; INSERM U1196, CNRS UMR9187, Centre Universitaire, Orsay 91405, France.
11
Université Paris Descartes, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Necker-Enfants Malades, Département Neurochirurgie pédiatrique, Paris, France.
12
Institut Curie, Paris 75248, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; SIREDO Center (Care, innovation, Research in pediatric, adolescent and young adult oncology), Institut Curie, Paris, France.
13
PSL Research University, Paris, France; Institut Curie, Paris 75248, France; INSERM U830, Paris 75248, France; SIREDO Center (Care, innovation, Research in pediatric, adolescent and young adult oncology), Institut Curie, Paris, France.
14
Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
15
PSL Research University, Paris, France; Institut Curie, Paris 75248, France; INSERM U830, Paris 75248, France; Translational Research in Pediatric Oncology, Institut Curie SiRIC, Paris, France; SIREDO Center (Care, innovation, Research in pediatric, adolescent and young adult oncology), Institut Curie, Paris, France.
16
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS325, Memphis, TN 38017, USA. Electronic address: paul.northcott@stjude.org.
17
Institut Curie - Recherche, Laboratoire 110, Centre Universitaire, Orsay Cedex 91405, France; INSERM U1021, Centre Universitaire, Orsay 91405, France; CNRS UMR 3347, Centre Universitaire, Orsay 91405, France; Université Paris Sud-11, 91405 Orsay, France; PSL Research University, Paris, France. Electronic address: celio.pouponnot@curie.fr.

Abstract

Cancer cells often express differentiation programs unrelated to their tissue of origin, although the contribution of these aberrant phenotypes to malignancy is poorly understood. An aggressive subgroup of medulloblastoma, a malignant pediatric brain tumor of the cerebellum, expresses a photoreceptor differentiation program normally expressed in the retina. We establish that two photoreceptor-specific transcription factors, NRL and CRX, are master regulators of this program and are required for tumor maintenance in this subgroup. Beyond photoreceptor lineage genes, we identify BCL-XL as a key transcriptional target of NRL and provide evidence substantiating anti-BCL therapy as a rational treatment opportunity for select MB patients. Our results highlight the utility of studying aberrant differentiation programs in cancer and their potential as selective therapeutic vulnerabilities.

KEYWORDS:

BCL2; CRX; MAF; NRL; apoptosis; medulloblastoma; photoreceptor; retina

PMID:
29533784
DOI:
10.1016/j.ccell.2018.02.006
[Indexed for MEDLINE]

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