A Compendium of Cancer Organoid Models for Diverse Cancer Type

Development of new cancer therapeutics and validation of pathogenetic mechanisms in cancer require representative laboratory models. However, existing model collections do not yet represent the full spectrum of diversity observed in human cancer. Recent technologies enable more efficient model derivation (e.g., tumor organoids), yet whether such models maintain the molecular states of the originating tumor in long term ex vivo expansion has not been systematically investigated. Here, we present the results of a large-scale international program—the Human Cancer Models Initiative (HCMI)—including 665 patient-derived models from tumors provided by 2,594 donors. The collection enables tumor/model comparisons by whole genome, exome, methylome and transcriptome analyses. It includes 522 models with comprehensive clinical data, 153 models of rare cancers, and 71 models derived from non-European populations. Analysis of 421 matched tumor/model pairs revealed a high degree of genetic (97.8%) and epigenetic (95%) concordance. In glioblastoma, single-nucleus RNA sequencing of 16 tumor/model pairs revealed cell differentiation state shifts induced by specific culture medium formulations. We characterize extrachromosomal DNA-based gene amplification and post-treatment mutational signatures, which provide opportunities to study mechanisms of resistance to therapy. This publicly available collection of models, with accompanying molecular and clinical characterization and integrative software tools, provides the cancer research community with a powerful resource for preclinical investigation of cancer pathogenesis and treatment response.