Neurodevelopmental hijacking of oligodendrocyte lineage programs drives glioblastoma infiltration

Yiyan Wu¹, Benson Z Wu¹, Yosef Ellenbogen², Joan B Y Kant³, Pengcheng Yu³, Xuyao Li³, Loïc Caloren³, Valentin Sotov³, Christine Tran³, Michelle Restrepo³, Michelle Kushida⁴, Shamini Ayyadhury⁵, Pathum Kossinna³, Ruth Lau⁶, Parnian Habibi⁶, Sheila Mansouri⁷, Johanna Regala³, Tanja Durbic³, Farzaneh Aboualizadeh³, Julissa Tsao³, Troy Ketela³, Trevor Pugh⁸, Marcus O Butler⁹, Ben X Wang³, Peter B Dirks¹⁰, Andrew Gao¹¹, Gelareh Zadeh¹², Federico Gaiti¹³

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
² Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada; MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada.
³ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
⁴ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
⁵ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Donnelly Centre, University of Toronto, Toronto, ON, Canada.
⁶ Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
⁷ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada.
⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Ontario Institute for Cancer Research, Toronto, ON, Canada.
⁹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada.
¹⁰ Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Developmental and Stem Cell Biology Department, The Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹² Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada; MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada; Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA. Electronic address: zadeh.gelareh@mayo.edu.
¹³ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Ontario Institute for Cancer Research, Toronto, ON, Canada; Vector Institute, Toronto, ON, Canada. Electronic address: federico.gaiti@uhn.ca.

PMID: 40381621
DOI: 10.1016/j.devcel.2025.04.022

Free article

Neurodevelopmental hijacking of oligodendrocyte lineage programs drives glioblastoma infiltration

Yiyan Wu et al. Dev Cell. 2025.

Free article

. 2025 Sep 22;60(18):2420-2433.e12.

doi: 10.1016/j.devcel.2025.04.022. Epub 2025 May 16.

Authors

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
² Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada; MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada.
³ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
⁴ Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
⁵ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Donnelly Centre, University of Toronto, Toronto, ON, Canada.
⁶ Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
⁷ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada.
⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Ontario Institute for Cancer Research, Toronto, ON, Canada.
⁹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada.
¹⁰ Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Developmental and Stem Cell Biology Department, The Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹² Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada; MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada; Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA. Electronic address: zadeh.gelareh@mayo.edu.
¹³ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Ontario Institute for Cancer Research, Toronto, ON, Canada; Vector Institute, Toronto, ON, Canada. Electronic address: federico.gaiti@uhn.ca.

PMID: 40381621
DOI: 10.1016/j.devcel.2025.04.022

Abstract

Glioblastoma (GBM) is an aggressive brain tumor with a highly invasive nature. Despite the clinical relevance of this behavior, the molecular underpinnings of infiltrating GBM cells in the peritumoral zone remain underexplored in patients. Here, we show that peritumoral progenitor-like GBM cells activate transcriptional programs associated with increased invasivity, synaptic activity, and NOTCH signaling. These cells spatially colocalize with neurons and exhibit an increased propensity for neuronal crosstalk. The epigenetic encoding of these infiltrative cells mirrors that of uncommitted oligodendrocyte progenitor cells (OPCs) in the developing human brain, a neurodevelopmental state marked by increased synaptic and migratory potential. Functional perturbation of a nominated regulatory factor, ZEB1, confirmed its role in maintaining the invasive and uncommitted developmental potential of infiltrative GBM cells. Our findings provide insights into the neurodevelopmental hijacking that drives GBM infiltration in patients, rationalizing further investigation into targeting differentiation potential as a therapeutic strategy.

Keywords: GBM; cancer neuroscience; epigenomics; glioblastoma; intra-tumoral heterogeneity; invasion; neuron-tumor interaction; plasticity; single-cell omics.

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Conflict of interest statement

Declaration of interests F.G. serves as a consultant for S2 Genomics Inc. S.A. serves as a consultant for Pathomics Inc.

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Neurodevelopmental hijacking of oligodendrocyte lineage programs drives glioblastoma infiltration

Affiliations

Neurodevelopmental hijacking of oligodendrocyte lineage programs drives glioblastoma infiltration

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

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LinkOut - more resources

Full Text Sources

Medical