Abstract
Cholangiocarcinoma (CC) is an aggressive malignancy with an inferior prognosis due to limited systemic treatment options. As preclinical models such as CC cell lines are extremely rare, this manuscript reports a protocol of cholangiocarcinoma patient-derived organoid culture as well as a protocol for the transition of 3D organoid lines to 2D cell lines. Tissue samples of non-cancer bile duct and cholangiocarcinoma were obtained during surgical resection. Organoid lines were generated following a standardized protocol. 2D cell lines were generated from established organoid lines following a novel protocol. Subcutaneous and orthotopic patient-derived xenografts were generated from CC organoid lines, histologically examined, and treated using standard CC protocols. Therapeutic responses of organoids and 2D cell lines were examined using standard CC agents. Next-generation exome and RNA sequencing was performed on primary tumors and CC organoid lines. Patient-derived organoids closely recapitulated the original features of the primary tumors on multiple levels. Treatment experiments demonstrated that patient-derived organoids of cholangiocarcinoma and organoid-derived xenografts can be used for the evaluation of novel treatments and may therefore be used in personalized oncology approaches. In summary, this study establishes cholangiocarcinoma organoids and organoid-derived cell lines, thus expanding translational research resources of cholangiocarcinoma.
Highlights
Cholangiocarcinoma (CC) presents a heterogeneous group of malignancies originating from the biliary epithelium accounting for about 3% of all gastrointestinal cancers.According to its anatomical location, CC can be classified into distal, perihilarand intrahepatic tumors [1,2]
We aimed to a standardized protocol for obtaining organoid aimed to establish a standardized protocol fordigestion obtaining of organoid cultures from
To illustrate the consistency of histologic architecture, we examined the IHC profiles of our patient-derived organoids (PDOs) and corresponding xenografts compared to their primary tumors
Summary
Cholangiocarcinoma (CC) presents a heterogeneous group of malignancies originating from the biliary epithelium accounting for about 3% of all gastrointestinal cancers.According to its anatomical location, CC can be classified into distal (dCC), perihilar (pCC)and intrahepatic (iCC) tumors [1,2]. According to its anatomical location, CC can be classified into distal (dCC), perihilar (pCC). ICC is the second most common primary liver cancer after hepatocellular carcinoma (HCC), it is the rarest subtype as most CC arises in the perihilar region (50–67% pCC, 27–42% dCC, 6–8% iCC) [3,4]. Biliary tract diseases leading to chronic inflammation such as primary sclerosing cholangitis, bile duct cysts, hepatolithiasis, or opisthorchiasis are known to increase the risk of CC [5,6]. The prognosis of CC remains dismal, with surgery being the only potentially curative treatment. In advanced CC, the availability of effective systemic treatment options is still limited [8]. Five-year overall survival is low, ranging from 2% (metastatic CC of any location) to 25 % (resectable iCC) [9]
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