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 Junior Group for

TRANSLATIONAL
NEURO
ONCOLOGY

"Es sind nicht die großen Worte, die in der Gemeinschaft Grundsätzliches bewegen: Es sind die vielen kleinen Taten der Einzelnen."

- Mildred Scheel (1932 - 1985)

"Science is not only about immediate answers but about the conviction that every experiment brings us closer to the unknown frontier."

- Ernst Boris Chain (1945)

Activities

RESEARCH FOCUS

 

 

 

 

 

 

 

Welcome to the Translational Neuro-Oncology Group, co-led by Dr. Tanja Buhlmann and Dr. Ann-Christin Hau. Our research focuses on the critical challenge of intra-tumoral heterogeneity in adult-type diffuse gliomas, a driving factor behind both tumor progression and therapy resistance (Cell, 2022; Cancer Res. 2024). In addition, gliomas are notoriously infiltrative, spreading deep into the surrounding brain tissue, making them particularly difficult to treat effectively.

Intra-tumoral heterogeneity manifests in various ways:

  1. Genetic heterogeneity, where multiple genetically distinct clones and sub-clones coexist within a single tumor (Acta Neuropathologica, 2020).

  2. Epigenetic heterogeneity, in which malignant glioma cells adopt developmental cellular hierarchies and occupy diverse epigenetically defined transcriptional states.

  3. Environmental heterogeneity, where tumor cells interact with their tumor microenvironment (TME) to form distinct niches such as perivascular, hypoxic, or invasive regions (Nat Commun., 2020; Cell, 2022).

Our group’s focus is on advanced pre-clinical modeling, using:

  • Patient-derived tumor organoids (PDTOs) to replicate human glioma and its complex molecular characteristics (Acta Neuropathologica, 2020; STAR Protoc., 2021).

  • Patient-derived orthotopic xenografts (PDOX) and iPSC-derived cortical organoids (COs) to model the tumor microenvironment and investigate tumor infiltration patterns.

 

To further understand glioma invasion mechanisms, we have conducted CRISPRa screenings to identify key genes involved in tumor spread and are actively testing their relevance in these ex vivo and in vivo models.

By creating more representative patient avatars, we aim to bridge the gap between preclinical success and clinical translation. This approach helps validate our genetic engineering and pharmacological screening strategies for targeting glioma's infiltrative behavior.

In addition, we are integrating the immune-cell compartment within these models to conduct co-clinical trials, aligning pre-clinical findings with patient outcomes. As part of the Senckenberg Institute of Neuro-Oncology, we are proud to contribute validation strategies to the world’s first-in-human clinical trial using CAR-NK cells to target HER2-positive glioblastoma (CAR2BRAIN, NCT03383978)​.

With cutting-edge models and a focus on overcoming the infiltrative nature of gliomas, we are pushing the boundaries of therapeutic development to target the core mechanisms driving tumor invasion and resistance.

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Multiplex immunofluorescence staining from glioma patient tissue used for organoid generation in collaboration with the Immunomonitoring Platform (link) led by Prof. K. Plate.

Projects

RESEARCH PROJECTS

A pre-clinical experimental platform - patient-derived brain tumor models

In collaboration with the Neurosurgery Unit in Frankfurt (Prof. Markus Czabanka and Dr. Thomas Broggini) and the Neuropathology Department within the Edinger Institute (Prof. Karl Plate and Dr. Katharina Weber), alongside the Diagnostics Team (Maika Dunst and Tatjana Starzetz), we have developed a robust workflow for the routine sampling of brain tumors, including glioma, meningioma, and metastasis, with autologous patient blood. With ethical approval (UCT-37-2020), we achieve high fidelity in organoid generation (over 80% success rate), using advanced culture techniques (Jacob et al., 2020 and Oudin et al., 2020).

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Our patient-derived organoids, complete with sex, age, and integrated molecular diagnosis annotations, undergo routine screening for DNA methylation and morphological characteristics. These organoids are ideal for co-culture assays, drug-screening, and functional profiling. Additionally, they can be implanted in vivo into immunodeficient mice to generate patient-derived orthotopic xenografts (PDOX) or ex vivo into iPSC-derived cerebral organoids (COs), providing superior model systems for studying therapeutic responses and bridging the gap between preclinical findings and clinical translation.

By recapitulating the complexity of patient tumors, our models represent a robust toolbox for understanding glioma biology and advancing neuro-oncology research. These ressource infrastructure project was funded by the MSNZ Frankfurt and is currently funded by the Frankfurt Cancer Institute (FCI).

Establishing an immunocompetent patient-derived tumor organoid model for acute
co-clinical trial efficacy in recurrent glioblastoma
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Glioblastoma (GB) remains one of the hardest cancers to treat, with limited success from current therapies. We're developing advanced immunocompetent patient-derived tumor organoid (PDTO) models to explore immune cell interactions within the tumor microenvironment (TME) in GB. By incorporating autologous immune cells and CAR-NK cells into these 3D models, we can more effectively test immunotherapies.

This approach allows us to assess immune-modulatory treatments and refine inclusion criteria for clinical trials, like the CAR2BRAIN trial. Our goal is to identify which patients are most likely to respond to combination therapies or immune checkpoint inhibitors, leading to better trial designs and more personalized treatments for GB patients. The project is funded by the 2024 Discovery and Development Grant from the FCI, and is led by our PhD student, Till König.

Chemical probe screening of Glioblastoma organoids under TME conditions

We are currently performing standardized screens using a chemical probe set provided by Susanne and Stefan Knapp from the Structural Genomics Consortium (SGC) in Frankfurt to identify compounds that induce lethality in primary glioblastoma stem cells (GSCs) under standard culture conditions. This includes dynamic measurements of proliferation, cytotoxicity, and cell death induction using Live-Cell Imaging, as well as endpoint assessments of cell death and viability.

We are also developing methods to transition to tumor microenvironment (TME) conditions, including serum depletion, glucose restriction, and hypoxia, using patient-derived tumor organoids. This will enable us to more accurately mimic oxygen and nutrient gradients in a personalized setting. The project, in collaboration with PD Dr. Anna L. Luger and the SGC, will advance to validate promising candidates with dose-response curves and test them in combination with standard radio- and chemotherapy treatments.

iPSC-derived cortical organoids for GB invasion and TME studies
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We use iPSC-derived cortical organoids (COs) to develop advanced preclinical models for studying GB invasion. Traditional 2D models oversimplify the complexity of the tumor microenvironment (TME), missing critical factors like extracellular matrix (ECM), immune responses, and angiogenesis that drive GB invasion. Our 3D organoids replicate human brain structures, enabling us to study how glioblastoma cells invade and interact with neurons and glial cells.

These ex vivo invasion models align with the 3R principles and aim to develop a sophisticated system that closely mimics the tumor progression, invasion, and treatment response observed in humans, potentially replacing animal experiments.

Dr. Tanja Buhlmann  leads this project, which is funded by GRADE. Youcef Dahmani, our PhD student, is currently working on this project. In the future, we plan to enhance these models further by integrating functional blood vessels and a dedicated immune compartment to better simulate the complete tumor microenvironment.

Epi-genetic mechanisms of glioblastoma cell invasion

To unravel the mechanisms behind glioblastoma invasion, we focus on how external stimuli are transmitted into the cell and how these signals might reshape the epigenetic landscape. In particular, we investigate DNA methylation—a process capable of modulating gene expression without altering the underlying DNA sequence—examining its stability and susceptibility to environmental factors.

By integrating data from transcriptomic and methylomic analyses, our goal is to understand how intrinsic cellular properties intersect with external influences to drive invasive behavior in glioblastoma. Through genome-wide CRISPR activation screens, we identify genes essential for this process and further assess how specific epigenetic modifications, such as DNA methylation, influence cellular invasion. Targeted interventions using CRISPR-based methylation and de-methylation strategies allow us to probe the functional consequences of these epigenetic changes. Our approach combines genome-wide CRISPR activation (CRISPRa) screens to identify essential invasion-related genes with functional assessments in glioblastoma-cerebral organoid (GB-CO) co-cultures.

Left: Video illustrating the preparation of cell culture work required for  transwell invasion assays for a genome-wide CRISPR activation screen.

Right: Live-cell imaging of GFP-labeled glioblastoma (GB) cells actively invading a cerebral organoid. The video captures the dynamic interaction between the GB cells and the 3D organoid environment, providing insights into invasive behavior.

Genetical engineering of human low-grade gliomas for pre-clinical model

Low-grade gliomas (LGGs) are slow-growing yet life-limiting brain tumors that primarily affect younger patients. Mutations in the isocitrate dehydrogenase 1 (IDH1) gene are characteristic of these tumors, alongside mutations in TP53 and ATRX in astrocytomas. Pre-clinical models of LGGs are limited, especially those that mimic early tumorigenesis. In this project, we aim to develop human induced pluripotent stem cell (hiPSC)-derived models of astrocytoma, a common glioma subtype. Using CRISPR-Cas9 genome editing, we sequentially introduced hallmark mutations—IDH1, TP53, and ATRX—into hiPSCs. This approach allows us to investigate the molecular mechanisms underlying glioma initiation and progression. The project involves electroporation optimization, molecular cloning of a Tet-inducible Cas9 system, and genetic manipulation of hiPSCs. The astrocytoma models generated will be used for studying tumor metabolism and identifying potential therapeutic targets. To model tumor growth in a more physiologically relevant environment, we will utilize cerebral organoids ("minibrains") for in vivo-like tumorigenesis. Initiated in collaboration with Prof. Dr. Barbara Klink from the National Center of Genetics at LNS, Luxembourg, this work seeks to provide a valuable platform for studying glioma biology and testing new treatment strategies. We are also offering master thesis opportunities focusing on key aspects of this project.

Correlative analysis of DNA methylation and protein expression

Our project investigates gliomas, including glioblastoma, astrocytoma, and oligodendroglioma, using a multi-omics approach to understand tumor heterogeneity. We analyze patient samples to study differences in gene expression related to tumor content and invasion zones.

We use formalin-fixed, paraffin-embedded (FFPE) samples for DNA methylation arrays and tissue microarrays. Tissue punches are taken from areas marked by HE staining to assess DNA methylation and protein expression patterns.

This project began at the Luxembourg Centre for Neuropathology (LCNP) with Prof. Michel Mittelbronn and PD Dr. Katrin Frauenknecht, and student Uxue Mata Salcedo. Currently, Anna Maria Fritz is leading the project, focusing on correlating differentially expressed gene promoters with protein expression and regional differences.

Our goal is to gain insights into glioma biology and identify potential biomarkers for improved diagnosis and treatment.

Team

TEAM

The Translational Neuro Oncology Group was established in December 2022 under the lead of Dr. Ann-Christin Hau. Together with Dr. Tanja Buhlmann (geb. Müller), they work as highly dynamic and ambitious scientific Duo resulting in a vibrant and inspiring scientific environment.

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Alumni

Hassan, Mostafa        MSc, Molecular Biotechnology, Hochschule Anhalt, Köthen

Richart, Lorraine       PhD, The Doctoral School in Science and Engineering, University of Luxembourg

Cohrs, Christoph        BSc, Applied biology for medicine and pharmacy, Hochschule Fresenius, Idstein

Adhikari, Aasha          MSc, Molekulare und Zelluläre Neurowissenschaften, Philipps-Universität Marburg

Khana, Devanshi        MSc, Physical Biology of Cells and Cell Interactions, J.W. Goethe-Universität Frankfurt am      Main

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CONTACT
 

Are you passionate about the molecular biology of brain tumors? Do you have a background in medicine or biology and want to contribute to cutting-edge research in neuro-oncology?

We’re always looking for motivated individuals to join us.

We offer exciting opportunities for internships, Master's, and PhD projects. Whether you're interested in molecular mechanisms, immunotherapy, glioma modeling, or exploring the latest techniques in cell biology and genetic engineering, you'll be part of a dynamic team pushing the boundaries of translational neuro-oncology.

Interested in applying? Please contact us and include a motivation letter, CV, and transcripts of records. We look forward to exploring how you can make a difference with us!

Translational Neuro-Oncology Group

Dr. Senckenbergisches Institut für Neuroonkologie &

Institute of Neurology (Edinger Institute)

University Hospital, Goethe University Frankfurt Heinrich-Hoffmann-Str. 7

60528 Frankfurt am Main

 

Building 89, Ground Floor, R014

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