Functional characterization of BAP1 mutations in genome edited cholangiocarcinoma organoids: Role in cell death and drug responses

TL;DR

This study shows that BAP1 mutations in cholangiocarcinoma organoids affect cell death and drug response, suggesting BAP1 could help predict treatment outcomes.

Contribution

The study functionally characterizes BAP1 mutations in genome-edited cholangiocarcinoma organoids, revealing their role in cell death and drug sensitivity.

Findings

BAP1-mutant organoids show impaired apoptosis and necroptosis activation.

BAP1 mutations alter gene expression related to stress and detoxification pathways.

BAP1 mutant organoids are more sensitive to the drug sorafenib.

Abstract

Cholangiocarcinoma (CCA) is a genetically heterogeneous malignancy of the bile ducts with limited effective treatments and variable chemotherapeutic responses. BRCA1-associated protein 1 (BAP1), a tumor suppressor gene frequently mutated in CCA, encodes a nuclear deubiquitinating enzyme involved in chromatin remodeling and cell death regulation. In this study, we investigated the role of BAP1 mutations in programmed cell death and drug response using patient-derived and prime-edited CCA organoids (CCAOs). BAP1-mutant organoids exhibited impaired activation of apoptosis and necroptosis, as evidenced by reduced cleaved caspase-3 and pMLKL expression. Transcriptomic analysis revealed BAP1-dependent gene expression changes including enrichment of pathways related to stress response, ion transport, and metabolic detoxification. Interesting, BAP1 mutant CCAOs showed enhanced sensitivity to sorafenib, a multikinase inhibitor commonly used in biliary tract cancer. These findings highlight BAP1 as a modulator of cell death and a potential predictive biomarker for sorafenib response in CCA, with implications for personalized therapy design.

•BAP1 mutation conveys resistance to apoptosis and necroptosis in CCAOs•BAP1 mutation induces transcriptome changes related to cellular stress and detoxification•BAP1 mutant cholangiocarcinoma organoids showed increased sensitivity to sorafenib

BAP1 mutation conveys resistance to apoptosis and necroptosis in CCAOs

BAP1 mutation induces transcriptome changes related to cellular stress and detoxification

BAP1 mutant cholangiocarcinoma organoids showed increased sensitivity to sorafenib

Pharmacology; Biochemistry; Cancer

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