Researchers have established a 256-organoid biobank derived from colorectal, oesophageal, ovarian, pancreatic and gastric tumours, using whole-genome sequencing and CRISPR–Cas9 screening to map gene dependencies.
Researchers have developed a new biobank containing 256 tumour organoids grown directly from patient cancer samples, providing a detailed resource for studying how different cancers depend on particular genes.
The study, published in Nature, involved tumour samples from patients with colorectal, oesophageal, ovarian, pancreatic and gastric cancers. Researchers established a network of clinical sites in Birmingham, Cambridge, Glasgow, London and Southampton to collect tumour tissue and associated patient information.
The resulting organoids were designed to be renewable and genetically stable, allowing scientists to study them over time and carry out experiments that would be difficult using patient tumours alone.
Mapping cancer dependencies
The team combined whole-genome and transcriptome sequencing with genome-wide CRISPR–Cas9 screening to investigate which genes cancer cells rely on to survive and grow.
CRISPR screening was carried out across 162 organoids, allowing the researchers to build a map of gene dependencies across different tumour types. The analysis identified both dependencies shared between cancers and vulnerabilities that appeared to be specific to particular organoids.
The researchers identified 654 core fitness genes shared between organoids and conventional cancer cell lines, while a further 97 were identified as unique to the organoid models.
Together, these results suggest that organoids can capture aspects of tumour biology that may be missed by traditional laboratory-grown cancer cell lines.
Potential treatment targets and tracking evolution
One of the study’s key findings involved the EGFR–RAS–MAPK signalling pathway, which plays an important role in colorectal cancer.
Researchers found that cancer cells carrying different KRAS mutations could have markedly different genetic dependencies. Organoids with KRAS G12X variants showed greater dependence on KRAS and upstream EGFR signalling than some other KRAS-mutant models.
Drug testing also revealed differences in how organoids responded to inhibitors targeting KRAS and EGFR, highlighting the potential importance of understanding the precise genetic characteristics of an individual tumour when considering treatment strategies.
The biobank also allowed researchers to compare tumour samples taken from the same patient before and after treatment.
In one case involving oesophageal cancer, organoids derived before chemotherapy were compared with those obtained after the tumour had relapsed. The researchers found changes in the tumour’s genetic dependencies that reflected its evolution under treatment pressure.
The post-treatment model showed reduced sensitivity to some RAS and DNMT1 inhibitors but increased sensitivity to proteasome inhibitors, suggesting that tumour evolution can create new vulnerabilities that may be exploitable therapeutically.
A resource for precision oncology
The researchers say the openly available biobank could provide scientists with a more representative set of tumour models for investigating cancer biology, testing drugs and identifying potential therapeutic targets.
The study concludes that the organoid collection and its dependency map represent a step towards creating more detailed, functionally informed maps of human cancer.
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