Patient-derived organoid biobanks preserve tumor heterogeneity and molecular signatures

Tumor heterogeneity-both within individual tumors and among different patients-poses a significant challenge for effective cancer treatment. To advance precision oncology, preclinical models that capture this complexity are essential. Patient-derived organoids (PDOs) provide a physiologically relevant platform that maintains the architecture and diversity of the original tumor, making them ideal for studying heterogeneity and patient-specific biology. In this study, we established and characterized PDO biobanks from colorectal and bladder cancers to evaluate their ability to represent intra-tumor heterogeneity and patient-specific molecular signatures. We profiled organoids using whole-exome sequencing and bulk RNA sequencing to assess their genomic and transcriptomic fidelity. Our analyses revealed that PDOs retain key mutational profiles and transcriptional programs of the original tumors, including subtype-specific signatures. Importantly, we observed distinct cellular subpopulations within individual PDO cultures that reflect intra-tumor diversity, including stem-like and differentiated phenotypes. These features persisted over time, confirming the stability of heterogeneity in vitro. Across the biobank, PDOs captured the spectrum of molecular subtypes present in colorectal and bladder cancers, enabling subtype-specific drug testing and biomarker discovery. This diversity highlights the potential of PDO platforms to model patient variability and inform personalized therapeutic strategies. Our findings demonstrate that PDOs are not only accurate representations of patient tumors but also dynamic systems that preserve heterogeneity at multiple levels. By integrating genomic and transcriptomic profiling with functional assays, PDO biobanks provide a powerful resource for studying tumor complexity and accelerating precision medicine.