The IL-6/JAK/STAT3 Axis in Cholangiocarcinoma and Primary Sclerosing Cholangitis: Unlocking Therapeutic Strategies Through Patient-Derived Organoids
<b>Background/Objectives:</b> Primary sclerosing cholangitis (PSC) is a rare, incurable liver disease characterized by chronic biliary inflammation and fibrosis. PSC is a significant risk factor for biliary tract cancer (BTC). This study aims to evaluate STAT3 expression in BTC and its p...
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2025-04-01
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| author | Corinna Boden Laura K. Esser Leona Dold Bettina Langhans Taotao Zhou Dominik J. Kaczmarek Maria A. Gonzalez-Carmona Tobias J. Weismüller Glen Kristiansen Jörg C. Kalff Michael Hölzel Hanno Matthaei Marieta I. Toma Vittorio Branchi |
| author_facet | Corinna Boden Laura K. Esser Leona Dold Bettina Langhans Taotao Zhou Dominik J. Kaczmarek Maria A. Gonzalez-Carmona Tobias J. Weismüller Glen Kristiansen Jörg C. Kalff Michael Hölzel Hanno Matthaei Marieta I. Toma Vittorio Branchi |
| author_sort | Corinna Boden |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> Primary sclerosing cholangitis (PSC) is a rare, incurable liver disease characterized by chronic biliary inflammation and fibrosis. PSC is a significant risk factor for biliary tract cancer (BTC). This study aims to evaluate STAT3 expression in BTC and its prognostic significance as well as explore the potential of organoids derived from PSC and liver tumor patients as an in vitro model for testing novel therapeutic strategies in both PSC and BTC. <b>Methods:</b> Fresh tissue samples obtained from 10 PSC patients through targeted endoscopic retrograde cholangiography (ERC) and biopsy samples from liver tumor patients were used to establish organoid cultures. Organoids were treated with different agents and the therapeutic effect was measured by CellTiterGlo. Treatment with the JAK inhibitor baricitinib was followed by the measurement of cytokine concentrations in the supernatant. Archived formalin-fixed paraffin-embedded (FFPE) samples from 55 surgically resected BTC tumors were analyzed for STAT3 expression using immunohistochemistry. <b>Results:</b> We successfully established organoid cultures from all ERC samples. STAT3 protein expression was detected in 56% of tumor samples and 69% of the immune microenvironment. STAT3 positivity in the immune cell compartment was associated with longer disease-free survival, although the multivariate analysis could not confirm its value as an independent prognostic factor. Chemotherapy testing on liver tumor organoids showed various degrees of decreases in viability after treatment with gemcitabine, cisplatin, and cabozantinib. Baricitinib treatment significantly reduced IL-6 and MCP-1 secretion in cholangiocarcinoma <b>Conclusions:</b> The patient-derived organoid model of PSC and liver tumors is a valuable tool for testing novel and established therapeutic strategies, including JAK inhibitors and chemotherapy regimens. STAT3 expression in the immune microenvironment of BTC may serve as a prognostic marker. Further studies are needed to explore the integration of co-cultured organoid systems with stromal and immune components to improve physiological relevance. |
| format | Article |
| id | doaj-art-448dafc9b21c457787dc6a1f1d734dfa |
| institution | Kabale University |
| issn | 2227-9059 |
| language | English |
| publishDate | 2025-04-01 |
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| series | Biomedicines |
| spelling | doaj-art-448dafc9b21c457787dc6a1f1d734dfa2025-08-20T03:47:50ZengMDPI AGBiomedicines2227-90592025-04-01135108310.3390/biomedicines13051083The IL-6/JAK/STAT3 Axis in Cholangiocarcinoma and Primary Sclerosing Cholangitis: Unlocking Therapeutic Strategies Through Patient-Derived OrganoidsCorinna Boden0Laura K. Esser1Leona Dold2Bettina Langhans3Taotao Zhou4Dominik J. Kaczmarek5Maria A. Gonzalez-Carmona6Tobias J. Weismüller7Glen Kristiansen8Jörg C. Kalff9Michael Hölzel10Hanno Matthaei11Marieta I. Toma12Vittorio Branchi13Department of General, Abdominal, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, GermanyInstitute of Pathology, University Hospital Bonn, 53127 Bonn, GermanyDepartment of Internal Medicine I, University Hospital Bonn, 53127 Bonn, GermanyDepartment of Internal Medicine I, University Hospital Bonn, 53127 Bonn, GermanyDepartment of Internal Medicine I, University Hospital Bonn, 53127 Bonn, GermanyDepartment of Internal Medicine I, University Hospital Bonn, 53127 Bonn, GermanyDepartment of Internal Medicine I, University Hospital Bonn, 53127 Bonn, GermanyVivantes Humboldt-Klinikum, 13509 Berlin, GermanyInstitute of Pathology, University Hospital Bonn, 53127 Bonn, GermanyDepartment of General, Abdominal, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, GermanyInstitute of Experimental Oncology, University Hospital Bonn, 53127 Bonn, GermanyDepartment of General, Abdominal, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, GermanyInstitute of Pathology, University Hospital Bonn, 53127 Bonn, GermanyDepartment of General, Abdominal, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany<b>Background/Objectives:</b> Primary sclerosing cholangitis (PSC) is a rare, incurable liver disease characterized by chronic biliary inflammation and fibrosis. PSC is a significant risk factor for biliary tract cancer (BTC). This study aims to evaluate STAT3 expression in BTC and its prognostic significance as well as explore the potential of organoids derived from PSC and liver tumor patients as an in vitro model for testing novel therapeutic strategies in both PSC and BTC. <b>Methods:</b> Fresh tissue samples obtained from 10 PSC patients through targeted endoscopic retrograde cholangiography (ERC) and biopsy samples from liver tumor patients were used to establish organoid cultures. Organoids were treated with different agents and the therapeutic effect was measured by CellTiterGlo. Treatment with the JAK inhibitor baricitinib was followed by the measurement of cytokine concentrations in the supernatant. Archived formalin-fixed paraffin-embedded (FFPE) samples from 55 surgically resected BTC tumors were analyzed for STAT3 expression using immunohistochemistry. <b>Results:</b> We successfully established organoid cultures from all ERC samples. STAT3 protein expression was detected in 56% of tumor samples and 69% of the immune microenvironment. STAT3 positivity in the immune cell compartment was associated with longer disease-free survival, although the multivariate analysis could not confirm its value as an independent prognostic factor. Chemotherapy testing on liver tumor organoids showed various degrees of decreases in viability after treatment with gemcitabine, cisplatin, and cabozantinib. Baricitinib treatment significantly reduced IL-6 and MCP-1 secretion in cholangiocarcinoma <b>Conclusions:</b> The patient-derived organoid model of PSC and liver tumors is a valuable tool for testing novel and established therapeutic strategies, including JAK inhibitors and chemotherapy regimens. STAT3 expression in the immune microenvironment of BTC may serve as a prognostic marker. Further studies are needed to explore the integration of co-cultured organoid systems with stromal and immune components to improve physiological relevance.https://www.mdpi.com/2227-9059/13/5/1083biliary tract cancercholangiocarcinomaprimary sclerosing cholangitisSTAT3baricitinib |
| spellingShingle | Corinna Boden Laura K. Esser Leona Dold Bettina Langhans Taotao Zhou Dominik J. Kaczmarek Maria A. Gonzalez-Carmona Tobias J. Weismüller Glen Kristiansen Jörg C. Kalff Michael Hölzel Hanno Matthaei Marieta I. Toma Vittorio Branchi The IL-6/JAK/STAT3 Axis in Cholangiocarcinoma and Primary Sclerosing Cholangitis: Unlocking Therapeutic Strategies Through Patient-Derived Organoids Biomedicines biliary tract cancer cholangiocarcinoma primary sclerosing cholangitis STAT3 baricitinib |
| title | The IL-6/JAK/STAT3 Axis in Cholangiocarcinoma and Primary Sclerosing Cholangitis: Unlocking Therapeutic Strategies Through Patient-Derived Organoids |
| title_full | The IL-6/JAK/STAT3 Axis in Cholangiocarcinoma and Primary Sclerosing Cholangitis: Unlocking Therapeutic Strategies Through Patient-Derived Organoids |
| title_fullStr | The IL-6/JAK/STAT3 Axis in Cholangiocarcinoma and Primary Sclerosing Cholangitis: Unlocking Therapeutic Strategies Through Patient-Derived Organoids |
| title_full_unstemmed | The IL-6/JAK/STAT3 Axis in Cholangiocarcinoma and Primary Sclerosing Cholangitis: Unlocking Therapeutic Strategies Through Patient-Derived Organoids |
| title_short | The IL-6/JAK/STAT3 Axis in Cholangiocarcinoma and Primary Sclerosing Cholangitis: Unlocking Therapeutic Strategies Through Patient-Derived Organoids |
| title_sort | il 6 jak stat3 axis in cholangiocarcinoma and primary sclerosing cholangitis unlocking therapeutic strategies through patient derived organoids |
| topic | biliary tract cancer cholangiocarcinoma primary sclerosing cholangitis STAT3 baricitinib |
| url | https://www.mdpi.com/2227-9059/13/5/1083 |
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