Credit: P. Morgan/Macmillan Publishers Limited

A biobank of patient-derived bladder cancer organoids that faithfully recapitulate the original tumour has been developed. Drug responses observed in organoids also occur in vivo, so these organoids could eventually be used to guide treatment decisions.

The biobank of organoids was established from fresh transurethral resection samples and the diversity of the organoids in the biobank is representative of the patient population from which it was generated. Overall, 16 organoid lines were established from 16 patients, multiple organoid lines were generated from 3 patients, representing chronologically distinct lesions. Established lines underwent multiple passages, cryopreservation, and recovery. Morphological concordance between the organoids and their parental tumours was strong. Histological analysis of organoid-derived xenografts and organoids derived from these xenografts showed that they were similar to the parental tumour.

The mutational profile of organoids and their parental tumours was highly concordant, and organoid mutations recapitulated the majority of common genomic alterations observed in human bladder cancer. Mutation profiles within individual organoid lines and their derivatives were also similar. Subclonal mutations were gained or lost during serial passaging, grafting, and/or re-establishment of organoids. Phylogenetic analysis showed linear and branched tumour evolution patterns, but the extent of evolution varied between organoid lines.

Organoid lines could be separated into two general categories: one group had strong phenotypic stability with similar marker expression profiles between the parental tumour, passaged organoids, xenografts, and xenograft-derived organoids; and the second group displayed considerable phenotypic differences between the parental tumours and organoids. In this second group, in most cases the parental tumour predominantly or exclusively expressed luminal markers, whereas the organoids lost luminal-marker expression and gained basal markers, but reverted back to a luminal phenotype when they were grown as xenografts. Organoids could be successfully categorized into basal or luminal subtypes using a molecular classifier based on human studies of bladder cancer, but several displayed a mixed phenotype.

Organoid response to bladder cancer drugs correlated with tumour progression. The mutational profiles of organoids could be used to predict additive drug responses. Validation of drug responses using xenograft studies showed that drug responses in culture were recapitulated in vivo.

Overall, this new biobank of bladder cancer organoids faithfully recapitulates the histology and molecular landscape of the original tumours and can be serially passaged, cryopreserved, and xenografted. In the future, these organoids could be used to aid treatment decisions for patients with bladder cancer.