Genomic analysis coupled with cancer organoid culture technology - building of next generation cancer cell models for therapeutic development

Abstract

Genomic analysis of gastrointestinal cancers, the most common cancer types worldwide, has revealed marked histological and molecular heterogeneity linked to different pathways of cancer development with therapeutic implications. For example, colorectal cancers that progress through serrated polyps are enriched for WNT upstream alterations, raising therapeutic opportunity through development of Wnt secretion inhibitors. Gastric cancers with chromosomal instability carry frequent diverse oncogenic driver amplifications that could be targeted by specific targeted agents. Because of these molecular diversity and potential differential mechanisms for aggressive behaviour and therapy resistance, good in vitro models that encompass unique subtypes are necessary for precision medicine development. We hence developed a primary gastric and colorectal cancer organoid culture biobank that includes normal, dysplastic, cancer and lymph node metastases from cancer patients that encompass most known molecular subtypes. The organoid cultures capture regional heterogeneity and subclonal architecture, remain closely similar to in vivo tumors by morphology, transcriptome and genomic profiles, that remained stable in long-term culture. Large-scale drug screening is possible that show differential sensitivity to drugs that can be linked back to patient drug response. Overall, coupling genomics and organoid-based drug screening, linking back to patient pathology and therapeutic response will empower the development of precision cancer therapy.