PhD Candidate University Hospital Tübingen Tübingen, Baden-Wurttemberg, Germany
Abstract: The treatment of primary and secondary brain cancers remains a major challenge, with median survival averaging only 10 months, despite advanced multimodal therapies. This highlights an urgent need for improved treatment strategies. However, drug development faces a critically low success rate of just 3–7%, largely due to inadequate preclinical models that fail to accurately replicate neurotoxicity and tumor microenvironment (TME) dynamics. To address this gap, we present a novel, highly modular murine ex vivo platform based on adult neural stem cells (aNSCs), designed for scalable, medium-throughput drug testing and mechanistic studies. This system integrates three distinct assembloid models: 1) Assembled Model – pre-grown cancer spheroids fuse with cerebral organoids to study tumor invasion and migration. 2) Cancer Core Model – distinct solid tumor cores embedded within healthy neural shells, closely mimicking in vivo-like tumor architectures. 3) Advanced Cancer Core Model – with immune cells, such as microglia, to investigate tumor–immune interactions within the TME. These assembloids form within 72 hours, offering a rapid, reproducible and ethical alternative to in vivo models. Their defined cellular composition and structured tissue architecture enhance translatability, overcoming batch variability in iPSC-derived organoids. Notably, the Cancer Core and Advanced Cancer Core Models are the first to feature a distinct, reproducible tumor core fully embedded in healthy neural tissue, enabling physiologically relevant studies of tumor growth, invasion and therapy response. By faithfully modeling aspects of the tumor–host interactions, this system supports in-depth investigations of tumor biology, drug efficacy and mechanisms of action. The immune-integrated Advanced Cancer Core Model further enables research on tumor–immune crosstalk and immunotherapy testing. Bridging in vitro and in vivo studies, this platform aligns with 3R principles, reducing reliance on animal models while maintaining biological complexity. By enhancing the predictive power of preclinical drug testing, these assembloids represent an innovative tool for brain cancer research, poised to accelerate bench-to-bedside translation.
Funding Source: Supported by Cenibra GmbH (AW, VA), Friedrich-Ebert-Stiftung, Joachim Herz Foundation and Bayer Foundation (AW), M3 Research Center, EXC2180 (iFIT), HECTOR Foundation. Thanks to OMNI Life Science for CERO 3D.
