Developing models of cholangiocarcinoma to close the translational gap in cancer research

ABSTRACT

Introduction: Cholangiocarcinoma (CCA) is an aggressive primary liver malignancy with abysmal prognosis and increasing global incidence. Individuals afflicted with CCA often remain asymptomatic until late stages of disease, resulting in very limited possibilities for therapeutic intervention. The emergence of numerous preclinical models in vitro and in vivo has expanded the tool kit for CCA researchers; nonetheless, how these tools can be best applied to understand CCA biology and accelerate drug development requires further scrutiny.

Areas covered: The paper reviews the literature on animal and organoid models of CCA (available through PubMed between September 2020 and January 2021) and examines their investigational role in CCA therapeutics. Finally, the potential of these systems for screening therapeutics to improve CCA patient outcomes is illuminated.

Expert Opinion: The expansion of CCA models has yielded a diverse and interesting tool kit for preclinical research. However, investigators should consider which tools are best suited to answer key preclinical questions for real progress. A combination of advanced in vitro cell systems and in vivo testing will be necessary to accelerate translational medicine in cholangiocarcinoma.

KEYWORDS:

• Cholangiocarcinoma
• organoid
• gemm
• therapeutic
• liver

Article highlights

• A range of human and rodent cell lines are available for CCA research; however, whether these are useful in accelerating translational research remains questionable.

• Cell of origin is hotly contested in CCA and it is perfectly possible that different CCAs can arise from hepatocytes and cholangiocytes.

• The best in vivo tools should reflect the disease history of CCA, where cancer forms on the background of repair.

• CCA genetics should inform the generation of new models of CCA. This is now achievable using CRISPR-Cas9.

• More complex in vitro tools will need developing to recapitulate the tumor stromal interactions found in CCA.

This box summarizes key points contained in the article.

Acknowledgments

L Boulter is funded by CRUK fellowship: C52499/A27948. All figures were generated using BioRender. We would like to thank Edmund Boulter-Comer for technical reading of the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose