Therapeutic radiation drives leptomeningeal dissemination of medulloblastoma through an innate immune process

Carolina Nör¹, Kaitlin Kharas², Alex Rasnitsyn³, Maria C Vladoiu², Nam Woo Cho⁴, Jacob S Young⁵, Felipe Nör⁶, Ncedile Mankahla⁷, Joonas Haapasalo⁷, Kristiina Nordfors⁷, Sara Rapic⁸, Patryk Skowron⁷, Raúl A Suárez⁷, Alexander T Bahcheli⁹, Oliver Ocsenas¹⁰, Xin Chen⁷, Shahrzad Bahrampour⁷, Ali Momin⁷, Lakshmikirupa Sundaresan⁷, Winnie Ong², Liam D Hendrikse³, Namal Abeysundara⁷, Kyle Juraschka², Michelle Ly², Jonelle G Pallota⁷, Tajana Douglas⁷, Ning Huang⁷, Hao Wang⁷, Esta Mak⁷, Lei Qin⁷, Jessica Liu⁷, Lily Shen⁷, Betty Luu⁷, Alex Manno⁷, Sachin A Kumar², Laura K Donovan⁷, Vernon Fong², Cory Richman³, Craig Daniels¹¹, Livia Garzia¹², Jeremy N Rich¹³, Cynthia Hawkins¹⁴, Xiaochong Wu¹¹, Ralph DaCosta¹⁵, Jüri Reimand¹⁶, Xi Huang¹⁷, Vijay Ramaswamy¹⁸, David R Raleigh¹⁹, Michael D Taylor²⁰

Affiliations

¹ Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Centre, Hospital for Sick Children, Toronto, ON, Canada. Electronic address: carolina.nor@sickkids.ca.
² Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
³ Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁴ Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA; Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
⁶ Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
⁷ Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Centre, Hospital for Sick Children, Toronto, ON, Canada.
⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
⁹ Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
¹¹ Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Centre, 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.
¹² Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada.
¹³ Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
¹⁴ Arthur and Sonia Labatt Brain Tumour Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹⁵ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
¹⁶ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁷ Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁸ Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada. Electronic address: vijay.ramaswamy@sickkids.ca.
¹⁹ Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. Electronic address: david.raleigh@ucsf.edu.
²⁰ Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Medical Biophysics, 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; Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada; Dan L Duncan Comprehensive Cancer Center, 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. Electronic address: michael.taylor@bcm.edu.

PMID: 40609543
DOI: 10.1016/j.devcel.2025.06.016

Therapeutic radiation drives leptomeningeal dissemination of medulloblastoma through an innate immune process

Carolina Nör et al. Dev Cell. 2025.

. 2025 Nov 3;60(21):2880-2896.e7.

doi: 10.1016/j.devcel.2025.06.016. Epub 2025 Jul 2.

Authors

Affiliations

¹ Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Centre, Hospital for Sick Children, Toronto, ON, Canada. Electronic address: carolina.nor@sickkids.ca.
² Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
³ Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁴ Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA; Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
⁶ Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
⁷ Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Centre, Hospital for Sick Children, Toronto, ON, Canada.
⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
⁹ Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
¹¹ Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Centre, 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.
¹² Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada.
¹³ Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
¹⁴ Arthur and Sonia Labatt Brain Tumour Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹⁵ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
¹⁶ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁷ Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁸ Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada. Electronic address: vijay.ramaswamy@sickkids.ca.
¹⁹ Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. Electronic address: david.raleigh@ucsf.edu.
²⁰ Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Medical Biophysics, 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; Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada; Dan L Duncan Comprehensive Cancer Center, 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. Electronic address: michael.taylor@bcm.edu.

PMID: 40609543
DOI: 10.1016/j.devcel.2025.06.016

Abstract

Leptomeningeal metastases are the most important source of morbidity and mortality for medulloblastoma patients. Radiation of the entire brain is highly effective in the treatment and/or prevention of medulloblastoma leptomeningeal metastases. Infants treated on clinical trials with focal tumor radiation recur metastatically, whereas infants treated with only chemotherapy relapse locally. In murine medulloblastoma model systems, provision of a single dose of radiation to the tumor drives leptomeningeal dissemination. An inflammatory response after radiation-induced tumor cell death recruits a variety of immune cells. Inflammation opens the local blood-brain barrier, allowing intravasation of medulloblastoma cells. Experimental induction of inflammation with lipopolysaccharide drives medulloblastoma leptomeningeal dissemination, whereas premedication with corticosteroids prevents both inflammation and the pro-metastatic effect of radiation. In murine model systems, inflammation in the tumor microenvironment secondary to external beam radiation is both sufficient and necessary to drive leptomeningeal metastases.

Keywords: cytokines; dexamethasone; inflammation; leptomeningeal metastasis; medulloblastoma; metastasis; radiation.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Therapeutic radiation drives leptomeningeal dissemination of medulloblastoma through an innate immune process

Affiliations

Therapeutic radiation drives leptomeningeal dissemination of medulloblastoma through an innate immune process

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources