Inhibition of Dopamine Receptor D1 Signaling Promotes Human Bile Duct Cancer Progression via WNT signaling

概要

Bile duct cancer (BDC) frequently invades the nerve fibers, making complete surgical resection difficult. A single tumor mass contains cells of variable malignancy and
cell-­differentiation states, with cancer stem cells (CSCs) considered responsible for
poor clinical outcomes. This study aimed to investigate the contribution of autosynthesized dopamine to CSC-­related properties in BDC. Sphere formation assays using
13 commercially available BDC cell lines demonstrated that blocking dopamine receptor D1 (DRD1) signaling promoted CSC-­related anchorage-­independent growth.
Additionally, we newly established four new BDC patient-­derived organoids (PDOs)
and found that blocking DRD1 increased resistance to chemotherapy and enabled
xenotransplantation in vivo. Single-­cell analysis revealed that the BDC PDO cells varied in their cell-­differentiation states and responses to dopamine signaling. Further,
DRD1 inhibition increased WNT7B expression in cells with bile duct-­like phenotype,
and it induced proliferation of other cell types expressing Wnt receptors and stem
cell-­like signatures. Reagents that inhibited Wnt function canceled the effect of DRD1
inhibition and reduced cell proliferation in BDC PDOs. ...

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