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To further assess neuronal function and maturity, the derived sensory neurons will be co-cultured with primary human Schwann cells (SCs), allowing for a more accurate evaluation of neuronal function and enhancing the model’s physiological relevance. The model will then be extended to include pancreatic cancer cells, enabling the study of nerve–tumor interactions in a human-based environment.
By developing a reliable source of human sensory neurons, Katharina’s work lays the foundation for future studies into the neurobiology of PDAC. Her project not only addresses a significant technical gap but also paves the way for better understanding how nerves influence cancer progression—and ultimately for developing more effective, targeted therapies for this devastating disease.
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Novel 3D ex vivo Culture for High-Throughput Drug Screening in Pancreatic Ductal Adenocarcinoma
27 March 2025
As part of her master’s thesis, Cheyenne Prat-Marques, a molecular biomedicine student, has joined our “PDAC-taskforce” to contribute to advancing preclinical drug discovery in pancreatic ductal adenocarcinoma (PDAC). This cancer remains one of the deadliest, with a five-year survival rate of only 13%. Current standard-of-care treatments, such as FOLFIRINOX or gemcitabine + nab-paclitaxel, provide only limited survival benefits due to therapy resistance driven by the immunosuppressive and highly fibrotic tumor microenvironment (TME). Therefore, new therapeutic approaches are urgently needed.
A major challenge in drug development is the lack of physiologically relevant preclinical models. Current approaches - including human 2D tumor cultures, organoids and mouse xenograft models - fail to fully capture the complexity of the native TME, limiting their predictive value for drug responses. To address this, Cheyenne is collaborating with the Institute of Pathology to establish an ex vivo drug-testing platform that preserves the native tumor architecture. This cutting-edge approach could be a milestone in overcoming current preclinical limitations, allowing for more accurate drug screening and a deeper understanding of therapy resistance mechanisms.
The fundamental objective of Cheyenne’s project is the establishment of an ex vivo culture that recapitulates the complete TME, enabling high-throughput screening for potential therapeutic vulnerabilities. Furthermore, high-resolution 3D imaging of the entire tumor will facilitate a detailed characterization of the heterogeneous cell populations within the TME. By bridging the gap between preclinical research and clinical application, this project has the potential to pave the way for more effective, personalized treatments for PDAC patients.
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New publication in Lab on a Chip
4 March 2025
Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer. One major cause for a fast disease progression is the presence of a highly fibrotic tumor microenvironment (TME) mainly composed of cancer-associated fibroblasts (CAF), and various immune cells, especially tumor-associated macrophages (TAM). To conclusively evaluate drug efficacy, it is crucial to develop in vitro models that can recapitulate the cross talk between tumor cells and the surrounding stroma. Here, we constructed a fit-for-purpose biochip platform which allows the integration of PDAC spheroids (composed of PANC-1 cells and pancreatic stellate cells (PSC)). Additionally, the chip design enables dynamic administration of drugs or immune cells via a layer of human umbilical vein endothelial cells (HUVEC). As a proof-of-concept for drug administration, vorinostat, an FDA-approved histone deacetylase inhibitor for cutaneous T cell lymphoma (CTCL), subjected via continuous flow for 72 h, resulted in a significantly reduced viability of PDAC spheroids without affecting vascular integrity. Furthermore, dynamic perfusion with peripheral mononuclear blood cells (PBMC)-derived monocytes resulted in an immune cell migration through the endothelium into the spheroids. After 72 h of infiltration, monocytes differentiated into macrophages which polarized into the M2 phenotype. The polarization into M2 macrophages persisted for at least 168 h, verified by expression of the M2 marker CD163 which increased from 72 h to 168 h, while the M1 markers CD86 and HLA-DR were significantly downregulated. Overall, the described spheroid-on-chip model allows the evaluation of novel therapeutic strategies by mimicking and targeting the complex TME of PDAC.