Early rhombic lip Protogenin+ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma

Abhirami Visvanathan; Olivier Saulnier; Chuan Chen; Parthiv Haldipur; Wilda Orisme; Alberto Delaidelli; Seungmin Shin; Jake Millman; Andrew Bryant; Namal Abeysundara; Xujia Wu; Liam D Hendrikse; Vikas Patil; Zahedeh Bashardanesh; Joseph Golser; Bryn G Livingston; Takuma Nakashima; Yusuke Funakoshi; Winnie Ong; Alexandra Rasnitsyn; Kimberly A Aldinger; Cory M Richman; Randy Van Ommeren; John J Y Lee; Michelle Ly; Maria C Vladoiu; Kaitlin Kharas; Polina Balin; Anders W Erickson; Vernon Fong; Jiao Zhang; Raúl A Suárez; Hao Wang; Ning Huang; Jonelle G Pallota; Tajana Douglas; Joonas Haapasalo; Ferechte Razavi; Evelina Silvestri; Olga Sirbu; Samantha Worme; Michelle M Kameda-Smith; Xiaochong Wu; Craig Daniels; Antony K MichaelRaj; Aparna Bhaduri; Daniel Schramek; Hiromichi Suzuki; Livia Garzia; Nabil Ahmed; Claudia L Kleinman; Lincoln D Stein; Peter Dirks; Christopher Dunham; Nada Jabado; Jeremy N Rich; Wei Li; Poul H Sorensen; Robert J Wechsler-Reya; William A Weiss; Kathleen J Millen; David W Ellison; Dimiter S Dimitrov; Michael D Taylor

doi:10.1016/j.cell.2024.06.011

Early rhombic lip Protogenin^+ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma

Cell. 2024 Aug 22;187(17):4733-4750.e26. doi: 10.1016/j.cell.2024.06.011. Epub 2024 Jul 5.

Authors

Abhirami Visvanathan¹, Olivier Saulnier², Chuan Chen³, Parthiv Haldipur⁴, Wilda Orisme⁵, Alberto Delaidelli⁶, Seungmin Shin³, Jake Millman⁴, Andrew Bryant⁷, Namal Abeysundara¹, Xujia Wu⁸, Liam D Hendrikse⁹, Vikas Patil¹⁰, Zahedeh Bashardanesh¹¹, Joseph Golser⁴, Bryn G Livingston¹², Takuma Nakashima¹³, Yusuke Funakoshi¹³, Winnie Ong¹², Alexandra Rasnitsyn⁹, Kimberly A Aldinger¹⁴, Cory M Richman⁹, Randy Van Ommeren¹², John J Y Lee¹², Michelle Ly¹², Maria C Vladoiu¹², Kaitlin Kharas¹², Polina Balin¹², Anders W Erickson¹², Vernon Fong¹², Jiao Zhang¹⁵, Raúl A Suárez¹, Hao Wang¹, Ning Huang¹, Jonelle G Pallota¹, Tajana Douglas¹, Joonas Haapasalo¹⁶, Ferechte Razavi¹⁷, Evelina Silvestri¹⁸, Olga Sirbu⁹, Samantha Worme¹⁹, Michelle M Kameda-Smith²⁰, Xiaochong Wu¹⁵, Craig Daniels¹⁵, Antony K MichaelRaj²¹, Aparna Bhaduri²², Daniel Schramek²³, Hiromichi Suzuki¹³, Livia Garzia²⁴, Nabil Ahmed²⁵, Claudia L Kleinman²⁶, Lincoln D Stein²⁷, Peter Dirks²⁸, Christopher Dunham²⁹, Nada Jabado³⁰, Jeremy N Rich⁸, Wei Li³, Poul H Sorensen⁶, Robert J Wechsler-Reya³¹, William A Weiss³², Kathleen J Millen³³, David W Ellison⁵, Dimiter S Dimitrov³⁴, Michael D Taylor³⁵

Affiliations

¹ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
² The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Genomics and Development of Childhood Cancers, Institut Curie, PSL University, 75005 Paris, France; INSERM U830, Cancer Heterogeneity Instability and Plasticity, Institut Curie, PSL University, 75005 Paris, France; SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, 75005 Paris, France.
³ Center for Antibody Therapeutics, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁴ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
⁵ St. Jude Children's Research Hospital, Memphis, TN, USA.
⁶ British Columbia Cancer Agency, Vancouver, BC, Canada.
⁷ Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
⁸ Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁹ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
¹⁰ MacFeeters-Hamilton Center for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
¹¹ Lady Davis Institute, McGill University, Montreal, QC, Canada.
¹² The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹³ Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.
¹⁴ Departments of Pediatrics and Neurology. University of Washington, Seattle, WA, USA.
¹⁵ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Texas Children's Cancer and Hematology Center, Houston, TX, USA; Department of Pediatrics - Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA.
¹⁶ Department of Neurosurgery, Tampere University Hospital, Tampere, Finland.
¹⁷ Assistance Publique Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France.
¹⁸ Surgical Pathology Unit, San Camillo Forlanini Hospital, Rome, Italy.
¹⁹ Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
²⁰ Texas Children's Cancer and Hematology Center, Houston, TX, USA; Department of Pediatrics - Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA.
²¹ Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
²² Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
²³ Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
²⁴ Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC, Canada.
²⁵ Centre for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.
²⁶ Department of Human Genetics, McGill University, Montreal, QC, Canada; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC, Canada.
²⁷ Adaptive Oncology, Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
²⁸ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada.
²⁹ British Columbia Children's Hospital, Vancouver, BC, Canada.
³⁰ Departments of Pediatrics and Human Genetics, McGill University, Montreal, QC, Canada; The Research Institute of the McGill University Health Center, Montreal, QC, Canada.
³¹ Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
³² Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
³³ Department of Pediatrics, University of Washington, Seattle, USA.
³⁴ Center for Antibody Therapeutics, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: mit666666@pitt.edu.
³⁵ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Texas Children's Cancer and Hematology Center, Houston, TX, USA; Department of Pediatrics - Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA; Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA; Department of Neurosurgery, Texas Children's Hospital, Houston, TX, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA; Department of Surgery, University of Toronto, Toronto, ON, Canada. Electronic address: mdt.cns@gmail.com.

PMID: 38971152
DOI: 10.1016/j.cell.2024.06.011

Abstract

We identify a population of Protogenin-positive (PRTG^+ve) MYC^high NESTIN^low stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RL^VZ). Oncogenic transformation of early Prtg^+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG^+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RL^VZ, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTG^high compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RL^VZ PRTG^+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTG^high compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.

Keywords: brain development; brain tumor immunotherapy; cancer genomics; group 3 medulloblastoma; perivascular niche; rhombic lip.

MeSH terms

Animals
Cerebellar Neoplasms / metabolism
Cerebellar Neoplasms / pathology
Coculture Techniques
Embryonic Structures
Endothelial Cells / metabolism
Humans
Medulloblastoma* / metabolism
Medulloblastoma* / pathology
Metencephalon / embryology
Mice
Neoplastic Stem Cells* / metabolism
Neoplastic Stem Cells* / pathology
Rhombencephalon / embryology
Rhombencephalon / metabolism
Stem Cell Niche
Stem Cells / metabolism

Supplementary concepts

rhombic lip

Abstract

MeSH terms

Supplementary concepts

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