A blueprint for local and distal invasion programs in glioblastoma

Glioblastoma invasion into brain parenchyma presents significant challenges for treatment but remains poorly understood. In this study, we combine single-cell RNA sequencing, spatial transcriptomics, and multiplexed imaging of orthotopic xenograft models to investigate glioblastoma invasion. We first screen 20 patient-derived gliomasphere models for their distal (i.e., extending to the contralateral hemisphere) and local invasive potential in mice. We show that models with distal invasion potential are enriched with oligodendrocyte progenitor-like cells, while models with only local invasion potential are enriched with mesenchymal-like cells. These patterns reflect predominantly peri-axonal vs peri-vascular invasion routes, respectively. Next, we analyze the transcriptomes of invading cells within models (compared to tumor core) and identify programs associated with distal and local invasion. Thus, we decouple transcriptional features associated with invasion potential from those associated with the process of invasion. We validate our findings by spatial transcriptomics and multiplexed imaging, further describing the spatial niche of invasive cells. Taken together, our results provide a blueprint for the invasive potential of glioblastoma cell states and of the programs associated with invasion across different scales.

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Publication Details

Journal
Nature Communications
Published
2026-03-17
DOI
https://doi.org/10.1038/s41467-026-70470-8
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
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article

A blueprint for local and distal invasion programs in glioblastoma

Wajd Al-Holou, Rouven Hoefflin, Itay Tirosh, Hiroaki Wakimoto et al.
Nature Communications
Single-cell and spatial transcriptomics
article

A blueprint for local and distal invasion programs in glioblastoma

Wajd Al-Holou, Rouven Hoefflin, Itay Tirosh, Hiroaki Wakimoto, Ester Calvo Fernández, Toshiro Hara, Alissa Greenwald, Alexander Jucht, Avishay Spitzer, Rony Chanoch-Myers, Jinan Behnan, Lillian Bussema, Jeremy Man Hon Fung, Jahnavi Gurramkonda, Zhibek Bekezhankyzy, Edwin Nieblas-Bedolla, Mario L. Suvà, Rossella Galli, Hannah R. Weisman, Sandra Camelo-Piragua, Biella Chiara
article en

Abstract

Glioblastoma invasion into brain parenchyma presents significant challenges for treatment but remains poorly understood. In this study, we combine single-cell RNA sequencing, spatial transcriptomics, and multiplexed imaging of orthotopic xenograft models to investigate glioblastoma invasion. We first screen 20 patient-derived gliomasphere models for their distal (i.e., extending to the contralateral hemisphere) and local invasive potential in mice. We show that models with distal invasion potential are enriched with oligodendrocyte progenitor-like cells, while models with only local invasion potential are enriched with mesenchymal-like cells. These patterns reflect predominantly peri-axonal vs peri-vascular invasion routes, respectively. Next, we analyze the transcriptomes of invading cells within models (compared to tumor core) and identify programs associated with distal and local invasion. Thus, we decouple transcriptional features associated with invasion potential from those associated with the process of invasion. We validate our findings by spatial transcriptomics and multiplexed imaging, further describing the spatial niche of invasive cells. Taken together, our results provide a blueprint for the invasive potential of glioblastoma cell states and of the programs associated with invasion across different scales.

Nature Communications
Broad Institute (US), Mount Sinai Hospital (CA), Albert Einstein College of Medicine (US), Montefiore Medical Center (US), Harvard University (US), Vita-Salute San Raffaele University (IT), University of Freiburg (DE), Tel Aviv University (IL), University of Toronto (CA), Lunenfeld-Tanenbaum Research Institute (CA), University of Michigan (US), Tel Aviv Sourasky Medical Center (IL), Massachusetts General Hospital (US), Michigan Medicine (US), Dana-Farber Cancer Institute (US), Michigan Center for Translational Pathology (US), BioSurfaces (United States) (US), Center for Cancer Research (US), Neurological Surgery (US), Weizmann Institute of Science (IL)
Openalex Percentile: Top 19%
Single-cell and spatial transcriptomics
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