Glioblastoma is an aggressive brain tumor that infiltrates deep into the surrounding brain tissue. Even after surgery, tumor cells remain in the brain and the tumor recurs. Researchers at the University Hospital Bonn (UKB) and the University of Bonn have now developed Core2Edge, a model based entirely on human tissue that captures these hard-to-access infiltration zones at the tumor margin. The model enables investigation of the invasive front and direct assessment of new drug candidates in human tissue - without the need for animal testing. The study of the Brain Tumor Translational Research Group has now been published in Nature Protocols.

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. Core2Edge allows us to study these infiltrative tumor cells in a model based entirely on human tissue, closely mirroring what we see in patients."

Priv.-Doz. Dr. Matthias Schneider, Deputy Director, Department of Neurosurgery, UKB and Head of the Brain Tumor Translational Research Group, UKB and the University of Bonn

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).

Source:

Journal reference:

Melhem, A., et al. (2026). Core2Edge: a human glioblastoma organoid–brain slice model capturing infiltration and transcriptional heterogeneity from core to single-cell dispersion. Nature Protocols. DOI: 10.1038/s41596-026-01412-3. https://www.nature.com/articles/s41596-026-01412-3