Summary: Researchers have developed Core2Edge, an advanced human ex vivo tissue model that reproduces the invasive spread and molecular heterogeneity of glioblastoma.
By combining patient-derived glioblastoma organoids with organotypic human brain-slice cultures, this platform enables high-resolution spatial tracking of infiltrating tumor cells as they move into healthy brain tissue.
Core2Edge integrates expanded light-sheet fluorescence microscopy with spatial transcriptomics to map cell migration and gene expression at single-cell resolution. The model reproduces key patient-specific tumor behaviors, highlights potential therapeutic targets to limit recurrence, and provides a human-based alternative to animal models.
Key Facts
- Mechanistic driver of recurrence: Infiltrating glioblastoma cells migrate deep into healthy brain parenchyma, beyond the margins visible during surgery, and serve as a primary source of rapid tumor recurrence after treatment.
- Human-derived architecture: Core2Edge implants patient-derived glioblastoma organoids into live organotypic human brain slices obtained from tissue routinely removed during neurosurgery, modeling human-specific infiltration.
- High-resolution 3D visualization: Physical tissue expansion combined with light-sheet fluorescence microscopy produces whole-volume 3D reconstructions that resolve individual invasive cell morphologies at single-cell resolution.
- Preservation of heterogeneity: Spatial transcriptomics confirms that Core2Edge maintains complex intratumoral genetic heterogeneity across tissue zones, mirroring the diverse cellular states seen in glioblastoma patients.
- Ethical and translational advancement: Modeling glioblastoma invasion directly in human neural architecture reduces reliance on animal models while improving relevance for human disease and therapy development.
Source: University of Bonn
Glioblastoma is a malignant brain tumor and one of the most aggressive human cancers. Despite combined treatments—surgery, radiation, and chemotherapy—no cure exists. A major challenge is the tumor’s invasive nature: glioblastoma cells spread far beyond the visible tumor into otherwise healthy brain tissue. These infiltrating cells cannot be fully removed and often seed recurrence within months.
“To understand why glioblastoma returns, we must study 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 lets us study these infiltrative tumor cells in a model based entirely on human tissue, closely mirroring what we observe in patients,” Schneider adds.
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 samples—with organotypic human brain-slice cultures.
Slices are prepared from brain tissue routinely removed during neurosurgical access procedures and would otherwise be discarded. For Core2Edge, organoids are implanted into these slices and co-cultured with the surrounding tissue. This configuration allows researchers to follow tumor spread from the dense tumor core to individual infiltrating cells that migrate into distant brain regions.
To visualize invasion, the team uses high-resolution light-sheet fluorescence microscopy. After fixation, tissue is uniformly expanded to improve light penetration and reveal fine structures. The expanded sample is then scanned layer by layer to create three-dimensional images of the entire tumor-infiltrated brain volume down to single-cell detail.
“This method lets us quantify tumor cell spread in three dimensions and trace morphology to individual infiltrating cells,” explains first author Ahmad Melhem, who co-developed Core2Edge during his doctoral work.
“The approach provides a detailed view of the earliest invasion steps and the spatial arrangement of tumor cells invading human brain tissue.”
Beyond imaging, the team applied spatial transcriptomics to determine which genes are active in individual tumor cells and where those cells are located within the tissue.
This is especially important in glioblastoma because cells within a single tumor often display markedly different gene expression programs. This intratumoral heterogeneity drives therapy resistance: some cell populations survive radiation and chemotherapy better than others and can regenerate the tumor.
“We demonstrated that Core2Edge preserves intratumoral heterogeneity, providing further proof that the model reflects patient tumors,” says Dr. Anna-Laura Potthoff, neurosurgeon and clinician scientist at the Brain Tumor Translational Research Group.
Core2Edge lays the groundwork for investigations into which cellular programs are active in infiltration zones and which therapeutic targets could delay or prevent recurrence.
In addition to advancing glioblastoma research, the model reduces the need for animal experiments. “Because key features of glioblastoma biology—particularly infiltration and heterogeneity—can be studied directly in human tissue, Core2Edge is both a scientifically and ethically compelling alternative to animal models,” Schneider notes.
Scientists involved in Bonn: The study was performed by the Brain Tumor Translational Research Group (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), in collaboration with investigators across the University of Bonn and UKB research institutes.
Funding: The project received funding from the Mildred Scheel School of Oncology (MSSO) Cologne-Bonn of German Cancer Aid, the Ministry of Culture and Science of North Rhine-Westphalia as part of the CANTAR research network, and the German Research Foundation.
Key Questions Answered:
A: Traditional animal models and two-dimensional cultures lack the human-specific extracellular matrix and microenvironment found in the brain. Core2Edge uses human brain-slice cultures to observe true human tumor cell migration within native neural structures.
A: Dense neural tissue scatters light and limits deep imaging. Uniform expansion homogenizes refractive properties and separates structures physically, allowing light-sheet lasers to penetrate deep volumes and image single infiltrating cells in three dimensions without signal distortion.
A: Spatial transcriptomics maps active gene expression in individual cells while preserving their exact coordinates in the tissue slice. This reveals how glioblastoma cells change genetically as they move from the tumor core to the invasive edge and helps identify targets to eliminate drug-resistant invasive cells.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was added by staff.
About this brain cancer and neurotechnology research news
Author: Inka Väth
Source: Universitätsklinikum Bonn
Contact: Inka Väth – Universitätsklinikum Bonn
Image: Image 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 et al., published in 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 operate as complex cellular networks that extend into surrounding brain tissue, enabling long-range communication. This malignant connectivity spans from the tumor core to remote infiltration zones and supports the concept of glioblastoma as a disease affecting the whole brain.
With growing ethical concerns in biomedical research and the limitations of animal models in reproducing human glioblastoma biology, there is increasing demand for human ex vivo platforms that capture the full infiltration spectrum from tumor core to single-cell dispersion.
We present a 3D, fully human ex vivo glioblastoma model, Core2Edge, that replicates this wide infiltration range while preserving the original tumor’s intratumoral heterogeneity.
The model implants fluorescently labeled human glioblastoma organoids into organotypic human brain slices, maintaining genetic integrity and cytoarchitecture for both brain and tumor. Combining tissue expansion with light-sheet fluorescence microscopy enables high-resolution 3D imaging of the entire organoid–brain slice construct.
This approach enables study of early invasion steps, in-depth analysis of the invasive front, and exploration of tumor–microenvironment interactions. It also provides a platform for drug screening and testing that can reduce reliance on animal models. Once organoids are prepared, the protocol requires approximately 7–12 days, with key steps including brain slice preparation (~4–6 hours), a day for initial culture before organoid staining and transplantation, a variable co-culture period (up to 10 days), and fixation (~8 hours). The protocol requires experience in human brain slice and organoid culture.