Summary: Researchers developed “Core2Edge,” an advanced ex vivo human tissue model that replicates the invasive spread and molecular diversity of glioblastoma.
By combining patient-derived glioblastoma organoids with organotypic human brain-slice cultures, the platform enables high-resolution spatial tracking of infiltrating tumor cells into healthy brain tissue.
The model integrates expanded light-sheet fluorescence microscopy with spatial transcriptomics to map cell migration and gene expression at single-cell resolution. Core2Edge recapitulates critical patient-specific tumor dynamics, identifying potential therapeutic targets to prevent recurrence while offering a human-centric alternative to animal testing.
Key Facts
- Mechanistic Driver of Recurrence: Infiltrating glioblastoma cells migrate deep into healthy brain parenchyma beyond surgical margins, serving as the primary source for rapid tumor recurrence post-treatment.
- Integrated Human-Derived Architecture: Core2Edge implants patient-derived glioblastoma organoids into live organotypic human brain slices (derived from routinely discarded neurosurgical tissue) to model human-specific brain infiltration.
- High-Resolution 3D Visualization: The team combined physical tissue expansion with light-sheet fluorescence microscopy to generate whole-volume 3D reconstructions, resolving individual invasive cell morphologies at single-cell resolution.
- Recapitulation of Heterogeneity: Spatial transcriptomics confirmed that Core2Edge preserves complex intratumoral genetic heterogeneity across different tissue zones, mirroring distinct cellular states observed in glioblastoma patients.
- Ethical and Scientific Advancement: By modeling human glioblastoma invasion directly in human neural architecture, Core2Edge minimizes dependency on animal models while improving translational accuracy.
Source: University of Bonn
Glioblastoma is a malignant brain tumor and among the most aggressive cancers in humans. Despite multimodal therapy with surgery, radiation, and chemotherapy, there is still no cure. A major reason is the tumor’s invasive behavior: glioblastoma cells migrate far beyond the visible tumor into healthy brain tissue. These infiltrating cells cannot be completely removed and seed tumor recurrence – often within just a few months.
“To understand why glioblastoma keeps coming back, we need to look closely at the tumor cells that remain hidden in the brain after surgery,” says Priv.-Doz. Dr. Matthias Schneider, Deputy Director of the Department of Neurosurgery at the UKB and Head of the Brain Tumor Translational Research Group at the UKB and the University of Bonn.
“Core2Edge allows us to study these infiltrative tumor cells in a model based entirely on human tissue, closely mirroring what we see in patients.“
Core2Edge combines glioblastoma organoids with human brain tissue in a single model
The research team from the Departments of Neurosurgery and Neuro-Oncology at the UKB combines glioblastoma organoids – miniature tumor tissues grown from freshly resected patient material – with organotypic human brain-slice cultures.
The slices are prepared from brain tissue that is routinely removed during neurosurgical procedures to access deeper target regions and would otherwise be discarded. For Core2Edge, the organoids are implanted into the brain slices and co-cultured with the surrounding tissue. This allows tumor spread in human brain tissue to be tracked from the tumor core to individual infiltrating tumor cells, as they are found in brain regions distant from the solid tumor mass.
To visualize this process, the team uses high-resolution light-sheet fluorescence microscopy. After fixation, the tissue is first evenly expanded to improve light penetration and enhance the visibility of fine structures. The sample is then scanned layer by layer, creating three-dimensional images of the entire tumor-infiltrated brain volume – down to single-cell resolution.
“This allows us not only to quantify tumor cell spread in three dimensions, but also trace morphology down to individual infiltrating cells,” explains first author Ahmad Melhem, who co-developed the Core2Edge model as part of his doctoral research.
“This approach provides a detailed view of the earliest steps of invasion and the spatial organization of tumor cells infiltrating the human brain.”
In addition to high-resolution microscopy, the team also applied spatial transcriptomics. This technology reveals which genes are active in individual tumor cells and where exactly these cells are located in the tissue.
This is particularly important in glioblastoma, as glioblastoma cells differ markedly in their genetic activity states even within a single tumor. This so-called intratumoral heterogeneity is considered a key driver of therapy resistance: individual cell populations survive radiation and chemotherapy more effectively and give rise to renewed tumor growth.
“We were able to show that Core2Edge recapitulates intratumoral heterogeneity. This provides further evidence that the model closely reflects the situation in patients”, says Dr. Anna-Laura Potthoff, neurosurgeon and clinician scientist at the Brain Tumor Translational Research Group.
Core2Edge thus lays the foundation for future research into which cellular programs are active in the infiltration zones and which therapeutic targets may emerge to delay or prevent tumor recurrence.
Beyond its contribution to glioblastoma research, the model reduces reliance on animal experiments. “As key aspects of glioblastoma biology – especially infiltration and intratumoral heterogeneity – can be studied directly in human tissue, Core2Edge offers a scientifically and ethically compelling alternative to animal models,” Schneider says.
Scientists involved in Bonn: The study of the Brain Tumor Translational Research Group from the Department of Neurosurgery (Director: Prof. Dr. Hartmut Vatter), the Department of Neuro-Oncology (Director: Prof. Dr. Ulrich Herrlinger) and the Department of Neuropathology (Director: Prof. Dr. Torsten Pietsch) was carried out in collaboration with Dr. Juan E. Rodriguez Gatica and Prof. Dr. Ulrich Kubitscheck (both Clausius Institute for Physical and Theoretical Chemistry, University of Bonn), Prof. Dr. Andreas Schlitzer (Life & Medical Sciences Institute (LIMES), University of Bonn), Dr. Martin Schwarz (Institute for Experimental Epileptology and Cognitive Research, UKB), and Prof. Dr. Michael Hölzel (Institute for Experimental Oncology (IEO), UKB).
Funding: The project was funded by the Mildred Scheel School of Oncology (MSSO) Cologne-Bonn of German Cancer Aid, by the Ministry of Culture and Science of North Rhine-Westphalia as part of the CANTAR (CANcer TARgeting) research network, and by the German Research Foundation.
Key Questions Answered:
A: Traditional animal models and two-dimensional cell cultures lack human-specific extracellular matrix architectures and biological microenvironments. Core2Edge overcomes this by using human brain-slice cultures, allowing researchers to observe true human tumor cell migration within native neural tissue structures.
A: Dense neural tissue scatters light, obstructing high-resolution imaging in deep samples. Uniform tissue expansion homogenizes refractive indices and physically separates cellular structures, allowing light-sheet lasers to penetrate deep volumes and image single infiltrating glioblastoma cells in three dimensions without signal distortion.
A: Spatial transcriptomics allows researchers to map active gene expression programs in individual cells while maintaining their exact physical coordinates within the tissue slice. This reveals how glioblastoma cells adapt genetically as they transition from the solid tumor core to the invasive leading edge, aiding the discovery of therapies that target drug-resistant invasive cells.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this brain cancer and neurotech research news
Author: Inka Väth
Source: Universitatsklinikum Bonn
Contact: Inka Väth – Universitatsklinikum Bonn
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Core2Edge: A human glioblastoma organoid-brain slice model capturing infiltration and transcriptional heterogeneity from core to single-cell dispersion” by Ahmad Melhem, Barbara E. F. Pregler, Juan Eduardo Rodriguez-Gatica, Lea L. Friker, Jake Thomas, Marieta I. Toma, Mike-Andrew Westhoff, Vidhya M. Ravi, Valeri Borger, Dieter Henrik Heiland, Julian P. Layer, Andreas Schlitzer, Torsten Pietsch, Michael Hölzel, Andreas Waha, Hartmut Vatter, Martin K. Schwarz, Ulrich Herrlinger, Ulrich Kubitscheck, Anna-Laura Potthoff & Matthias Schneider. Nature Protocols
DOI:10.1038/s41596-026-01412-3
Abstract
Core2Edge: A human glioblastoma organoid-brain slice model capturing infiltration and transcriptional heterogeneity from core to single-cell dispersion
Glioblastomas function as intricate cellular networks that extend into the surrounding brain tissue, facilitating long-distance communication. This malignant connectivity spans from the tumor core to remote infiltration zones, in support of the concept of glioblastoma as a whole-brain disease.
With growing ethical concerns in biomedical research and the inherent limitations of animal models in recapitulating human glioblastoma biology, there is an increasing demand for human ex vivo platforms capable of capturing the full infiltration spectrum from the tumor core to single-cell dispersion.
Here we present a 3D, fully human ex vivo glioblastoma model (Core2Edge) that replicates this extensive infiltration range while preserving the intratumoral heterogeneity of the original tumor.
This model involves implanting fluorescently labeled human glioblastoma organoids (GBOs) into organotypic human brain slices, maintaining the genetic integrity and cytoarchitecture of both brain and tumor. By combining tissue expansion with light-sheet fluorescence microscopy, we achieve high-resolution, 3D imaging of the entire GBO–brain slice model.
This approach allows the study of initial infiltration steps, in-depth analysis of the invasive front, and exploration of cell–cell interactions between tumor cells and the tumor microenvironment, and offers a platform for drug screening and testing, reducing the need for animal models. Once GBOs are prepared, the protocol takes ~7–12 d.
Key steps include brain slice preparation (~4–6 h, depending on quantity), 1 d for initial culture before GBO staining and transplantation, a variable culture period (≤10 d), and fixation (~8 h). The protocol requires experience with human brain slice and organoid culture.
