This is a review focused on recent advances in the histopathological subtyping of biliary tract cancers (BTCs), discussing current genomic evidence and current knowledge surrounding the cell of origin of these tumors. BTCs represent an extremely heterogenous group of cancers with different anatomic location, risk factors, molecular features, and potentially distinct cells of origin. Of note, the critical question of which cell is responsible for cancer initiation remains unanswered and controversy exists. Future research will need to clarify the exact relationship between the cell of origin, tumor genotype, and immune microenvironment, providing the rationale for combining targeted therapies with immunotherapies and ultimately identifying potential predictive biomarkers. This is particularly relevant given that only a small fraction of patients benefits from currently available therapies. In this regard, the analysis of the tumor, immune and stroma compartment at the single cell level via single-cell RNA sequencing could provide critical information to clarify the role of the microenvironment in shaping distinct tumor phenotypes.

(Moeini, A. et al. – JHEP Rep, 19 January 2021)

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