Technology: Developing model systems to assess plasticity in cancer
Generation of patient-derived organoids
In the past, we have generated three-dimensional (3D) organoid cell cultures of mouse PDAC cells (Reichert et al., Nature Protocols 2013). With our expertise in 3D culture, we applied this technology to generate disease models directly from the patient. Over the past decade, organoid technology has reshaped biomedical and translational research in oncology and beyond. Importantly, tumor organoids maintain the genetic heterogeneity of the parenteral tumor, therefore these 3D structures represent a promising preclinical model system, particularly, for a heterogeneous cancer such as pancreatic cancer. Using this model system, we are able to make contributions to different areas in the field of cancer research including studies published in Cancer Cell, Nature Medicine, Gastroenterology, Cell Stem Cell, Nature Communications, Molecular Systems Biology, and Nature Biomedical Engineering.
Studying tumor morphogenesis and metastasis using patient-derived organoids in in vivo systems
To interrogate complex biological processes such as invasion and metastasis, we integrated patient-derived organoid (PDO) technology with in vivo models. Orthotopic transplantation of PDOs into the pancreas of immunocompromised mice generates PDOX tumors that closely recapitulate patient tumor histology and metastatic behavior (Dantes et al., JCI Insight, 2020). More recently, we established a PDO-on-chick chorioallantoic membrane (CAM) model, a scalable and naturally immunodeficient in vivo system that enables efficient analysis of tumor invasion and dissemination. PDO-derived tumors on the CAM faithfully reproduce the morphology of their parental tumors and metastasize to distant tissues, which can be quantitatively assessed using human-specific Alu sequence detection. This in ovo platform allows genetic and pharmacologic manipulation of patient-derived and murine PDAC organoids and supports medium-scale functional screening of metastatic capacity.
Single-cell phenotyping of PDAC to study intratumoral heterogeneity and EMT plasticity
We established digital holographic microscopy (DHM) as a label-free, high-throughput technology for functional characterization of pancreatic cancer cells (Wittenzellner et al., JCI Insight, 2025). DHM captures quantitative phase information derived from intracellular refractive index differences, providing rich single-cell–resolved phenotypic information. Coupling DHM with microfluidic systems enables high-throughput analysis of non-adherent single-cell suspensions. Using pixel-based machine learning approaches, we classify cells by identity, epithelial–mesenchymal transition status, or malignancy, and stratify pancreatic cancer patient-derived organoids into classical and quasi-mesenchymal subtypes, mirroring transcriptomic classifications. The technology is patented (Patent No.: EP20206259.2) and offers broad potential for scalable clinical translation.
Next-generation organoids to interrogate intratumoral heterogeneity in PDAC
In Papargyriou et al. (Nature Biomedical Engineering, 2025), we introduce a next-generation organoid platform designed to systematically capture and interrogate intratumoral heterogeneity in PDAC. By integrating advanced organoid engineering with high-content imaging and multi-modal molecular profiling, this approach enables parallel analysis of distinct tumor cell states in distinct PDAC subtypes. The platform preserves spatial, phenotypic, and functional diversity and allows quantitative linkage of cellular heterogeneity to therapeutic response. This work establishes next-generation organoids as a scalable and clinically relevant framework to dissect tumor complexity and to inform precision oncology strategies in PDAC.