Towards Next-Generation Cancer Cell Culture Models


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Mathew Garnett1
1The Wellcome Trust

Abstract

Background

Approximately 1,000 human cancer cell lines are available to scientists worldwide and these been used extensively in drug development. However, as we enter an era of precision medicine, poor representation of some cancer types, insufficient numbers to capture the genetic diversity of cancer, lack of clinical outcome data and lack of comparison to normal reference sample limits their use. Novel cell culturing methods such as organoid derivation have transformed our ability to derive cell models from both healthy and diseased tissue, and have the potential to overcome these limitations. I will present our efforts as part of the Human Cancer Model Initiative to create a new generation of molecularly-annotated cancer models as a community resource to catalyse future research. As an exemplar of our early efforts, I will present our recent work deriving a new set of long-term, self-propagating organoid models of oesophageal adenocarcinoma (EAC). The incidence of EAC is increasing while 5-year survival rates stagnate at less than 15%, and there is a lack of experimental models that recapitulate the pathology of EAC. Comparative analysis confirmed that EAC organoids recapitulate primary tumours at the level of morphology and genomic architecture, particularly polyclonality and mutational signatures. Extended culturing did not lead to the acquisition of cancer driver mutations; while the subclones displayed diverse clonal behaviours between cultures. EAC organoid models were amenable to medium throughput drug sensitivity testing and so have applications as a pre-clinical discovery tool to guide precision therapeutics.