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Cholangiolocellular carcinoma component (CLC) predicts a genetically and biologically distinct subgroup of mass-forming intrahepatic cholangiocarcinoma (MF-iCC).

ABSTRACT: Two molecular subgroups of MF-iCC were identified based on differentially expressed genes between MF-iCC with a cholangiolocellular carcinoma (CLC) component and those without a CLC component.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277546 | GEO | 2026/05/15

REPOSITORIES: GEO

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Project description:As genomic analysis technology has advanced, it has become possible to sub-classify intrahepatic cholangiocarcinoma (ICC) at the histological or molecular level. However, there are no truly representative models of ICC subtypes for use in studying developmental differences, carcinogenesis, and personalized drug response. Here, we sought to verify recent suggested two subgroup of ICC in organoids model, compare the characteristics between LD and SD type of ICC, and find the type-specific gene expression profile and targetable pathway as a therapeutic target. ICC organoids from 16 patients pathologically diagnosed with cholangiocarcinoma were prepared according to a previously established organoid culture protocol. ICC patients were subclassified into small-duct (SD) type and large-duct (LD) type according to histological characteristics and S100P, N-cadherin, and CD56 expression. ICC organoids were successfully established within one month and exhibited a morphology similar to that of their matching primary cancer. LD- and SD-type organoids exhibited histologic phenotypes and staining patterns characteristic of the corresponding ICC subtypes. ICC organoids showed high concordance of somatic mutations with primary tumors. Unsupervised principal component analysis clustering effectively separated each type of ICC. Differential gene expression revealed significant enrichment on KRAS, TGFβ and ERBB2 signaling pathways in LD-type compared with SD-type ICC (P<0.05). Gene set enrichment analysis further demonstrated that the cholangiocarcinoma class 2 signature, defined by Andersen et al., was significantly enriched in the LD-type (enrichment score=2.19, P<0.001). A protein-protein interaction network analysis identified ZNF217 as a significant hub protein (odds ratio=4.96, P=0.0105). We successfully performed prospective modeling of histological subtype specification using patient-derived ICC organoids. Moreover, gene expression profiling of ICC organoids enabled identification of type-specific targetable pathways.

Dataset Information

Cholangiolocellular carcinoma component (CLC) predicts a genetically and biologically distinct subgroup of mass-forming intrahepatic cholangiocarcinoma (MF-iCC).

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