Nature has published research detailing a UK initiative that created a biobank of 256 clinically annotated tumour organoids across five cancer types to systematically map cancer gene vulnerabilities.
Led by a network of five clinical sites in Birmingham, Cambridge, Glasgow, London, and Southampton, researchers gathered tissue samples alongside germline reference normal samples from 878 donors. Fresh tumour tissue was sent to the Wellcome Sanger Institute between May 2016 and November 2023 for centralized organoid derivation.
Derivation and genomic mapping
The project focused on five gastrointestinal and gynaecological cancers: colorectal, oesophageal, ovarian, pancreatic, and gastric adenocarcinomas. Overall, 256 organoid cultures were successfully established from 907 processed samples, representing a 28 percent derivation efficiency rate. When short-term cultures were included and low-cellularity samples excluded, the success rate reached 65 percent. Once banked, 93 percent of the cultures passed freeze-thaw quality control checks.
Whole-genome sequencing was conducted on all 256 organoid models, with patient-matched tumour tissue sequenced for 171 models. Genomic comparisons showed high correlation between organoids and parent tumours in mutational load, structural variants, and somatic copy number alterations. A subset of 133 models was derived as part of the Human Cancer Model Initiative.
Dependency screening
To map gene vulnerabilities, researchers performed genome-wide CRISPR-Cas9 screens across 162 organoid models cultured in a 5 percent basement membrane extract-2 suspension system. The screens used the minimal genome-wide CRISPR-Cas9 library, known as MinLibCas9, with 16 models also screened using the Yusa v1.1 library.
Using the BAGEL2 algorithm, the analysis identified a median of 1,440 fitness genes per organoid, with a range between 297 and 2,160. Data from the project has been made publicly accessible through the Cell Model Passports database, with models distributed through commercial and non-profit repositories.
