Cell of origin in biliary tract cancers and clinical implications

SUMMARY Biliary tract cancers (BTCs) are aggressive epithelial malignancies that can arise at any point of the biliary tree. Albeit rare, incidence and mortality rates have been rising steadily over the past 40 years, highlighting the need of improving current diagnosis and therapeutic strategies. BTCs show high inter- and intra-tumor heterogeneity both at the morphological and molecular level. Such complex heterogeneity poses a substantial obstacle to improving the outcome of these patients. It is widely accepted that the observed heterogeneity may be the result of a complex interplay of different elements, including risk factors, distinct molecular alterations and multiple potential cells of origin. The use of genetic lineage tracing systems in experimental models has identified cholangiocytes, hepatocytes and/or progenitor-like cells as the cell of origin of BTCs. Genomic evidence in support of the distinct cell of origin hypotheses is growing. In this review, we focus on recent advances in the histopathological subtyping of BTCs, discuss current genomic evidence and outline lineage tracing studies that have contributed to the current knowledge surrounding the cell of origin of these tumors.