Uncovering cantharidin's mechanism for cholangiocarcinoma treatment using patient-derived tumor organoids

Area of Science:

• Oncology
• Pharmacology
• Cancer Biology

Background:

• Cholangiocarcinoma (CCA) is a challenging cancer with limited effective treatments.
• Patient-derived organoids (PDOs) offer a promising preclinical model for studying cancer biology and drug response.

Purpose of the Study:

• To evaluate the antitumor efficacy of cantharidin in cholangiocarcinoma.
• To validate the predictive relevance of patient-derived organoids (PDOs) for drug sensitivity in CCA.
• To elucidate the molecular mechanisms underlying cantharidin's action in CCA.

Main Methods:

• Utilized patient-derived organoids (PDOs) that mimic the histological and genomic features of cholangiocarcinoma.
• Assessed cantharidin's efficacy against CCA PDOs and compared it with conventional chemotherapeutics.
• Investigated the effects of cantharidin on cell proliferation, apoptosis, and signaling pathways (p-ERK1/2-c-Fos).
• Correlated PDO drug sensitivity with clinical responses in five CCA patients.

Main Results:

• Cantharidin demonstrated significant inhibition of CCA PDO growth, comparable or superior to cisplatin.
• Drug sensitivity in PDOs showed perfect correlation with clinical patient responses, validating the model.
• Cantharidin suppressed proliferation and induced apoptosis via downregulation of the p-ERK1/2-c-Fos pathway.

Conclusions:

• Cantharidin exhibits potent antitumor activity against cholangiocarcinoma.
• Patient-derived organoids serve as a reliable model for predicting clinical drug response in CCA.
• Cantharidin's mechanism involves the p-ERK1/2-c-Fos signaling pathway, suggesting its potential as a targeted therapy for CCA.