A large international effort to develop patient-derived cancer models has found that most of the laboratory-grown models retain key molecular characteristics of the tumors from which they originated, including after extended periods in culture.
The findings, published in Nature, come from the Human Cancer Models Initiative (HCMI), a decade-long international research program supported in part by the National Cancer Institute. The initiative generated 665 next-generation laboratory models representing 25 cancer types from tissue donated by 2,780 patients enrolled in the project. The final collection includes models derived from 637 patients.
For laboratories using organoids and other advanced cell models, the findings provide data that can help researchers assess how faithfully an experimental system represents the original disease. Model fidelity has practical implications for experimental design, reproducibility, and the interpretation of results, particularly as labs integrate organoids into increasingly complex research workflows.
Models maintain strong molecular similarities
Researchers analyzed 421 tumors alongside their corresponding laboratory models to determine whether the models retained characteristics of the original tumors after long-term culture.
The analysis found 97.8 percent genetic concordance, 95 percent concordance in epigenetic features, and 92 percent transcriptional concordance. Most models had been maintained in culture for at least a year.
The researchers also examined several specific DNA characteristics, including driver mutations, mutational signatures, whole-genome doubling, and ploidy. Most models retained at least two, and often all four, of the characteristics evaluated.
The results provide additional evidence that well-characterized patient-derived models can remain representative of their source tumors over extended laboratory use. For lab managers overseeing these workflows, however, access to a validated model does not remove the need for robust quality control. Model authentication, consistent protocols, traceable reagents, defined culture conditions, and thorough documentation remain important for maintaining reproducibility as models move between experiments, researchers, and laboratories.
Culture conditions still require attention
Although the collection demonstrated strong overall fidelity, the study also identified exceptions in gene expression and cellular state. Single-nucleus RNA sequencing showed that culture conditions influenced cell states in some models, particularly those derived from glioblastoma.
Glioblastoma models grown in one medium retained more of the cellular heterogeneity of their parental tumors, while models grown under another condition shifted toward a mesenchymal cell state. The researchers did not observe similarly large effects from culture media across the other cancer lineages they examined.
That distinction has practical implications for laboratories using patient-derived models. The findings indicate that a model can remain genetically similar to its source tumor while culture conditions influence aspects of its transcriptional state. Labs therefore need to consider media and other culture parameters when standardizing protocols, comparing results across studies, or transferring models between research groups.
Standardization is already a broader challenge as organoids become more widely used. NIH established the Standardized Organoid Modeling Center in 2025 to develop standardized protocols and improve reproducibility in organoid research.
A resource for preclinical research
The HCMI collection includes 522 models with detailed clinical information, 153 models of rare cancers, and 71 models from people of primarily non-European ancestry. Researchers can search the collection based on factors including cancer type, treatment history, and demographic information.
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The models may also support research into therapeutic resistance. In glioblastoma, researchers identified genetic features associated with resistance to the chemotherapy drug temozolomide, including mutational signatures linked to previous treatment.
Validated models are being distributed through the American Type Culture Collection, with associated genomic, transcriptomic, epigenomic, and clinical information also available to researchers.
As human-derived and other advanced research models become a larger part of laboratory science, collections such as HCMI give labs access to extensively characterized materials. Their usefulness, however, also places greater emphasis on the operational systems surrounding them—from model selection and culture protocols to quality control, documentation, and data management.
This article was created with the assistance of Generative AI and has undergone editorial review before publishing.
