Adenosine Receptor 3 in Liver Cancer: Expression Variability, Epigenetic Modulation, and Enhanced Histone Deacetylase Inhibitor Effects
Background and Aims: Primary liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), has low response rates to existing treatments, highlighting the urgent need for novel treatment options. Adenosine A3 receptor (ADORA3) signaling has emerged as a potential target. Namod...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
|
| Series: | Gastro Hep Advances |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772572324001869 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850209229187579904 |
|---|---|
| author | Louise Kaldjob-Heinrich Sandro Nuciforo Steffen Lemke Aaron Stahl Stefan Czemmel Sepideh Babaei Lauriane Blukacz Marie-Anne Meier Yizheng Zhang Christian M. Schürch Irene Gonzalez-Menendez Pascal Woelffing Nisar P. Malek Veit Scheble Sven Nahnsen Manfred Claassen Markus Templin Hans Bösmüller Markus H. Heim Daniel Dauch Michael Bitzer |
| author_facet | Louise Kaldjob-Heinrich Sandro Nuciforo Steffen Lemke Aaron Stahl Stefan Czemmel Sepideh Babaei Lauriane Blukacz Marie-Anne Meier Yizheng Zhang Christian M. Schürch Irene Gonzalez-Menendez Pascal Woelffing Nisar P. Malek Veit Scheble Sven Nahnsen Manfred Claassen Markus Templin Hans Bösmüller Markus H. Heim Daniel Dauch Michael Bitzer |
| author_sort | Louise Kaldjob-Heinrich |
| collection | DOAJ |
| description | Background and Aims: Primary liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), has low response rates to existing treatments, highlighting the urgent need for novel treatment options. Adenosine A3 receptor (ADORA3) signaling has emerged as a potential target. Namodenoson, an ADORA3 agonist, has shown promise in early clinical trials for HCC. However, further data are required to clarify ADORA3 expression patterns in liver cancer, mechanisms of action, and the potential for combination therapies to inform patient selection for future clinical trials. Methods: Patient-derived tissue microarrays and RNA-sequencing were employed to investigate ADORA3 expression. Cellular responses to ADORA3 stimulation and combination treatments were studied in HCC and CCA cell lines and patient-derived organoids (PDOs). Genome-wide RNA-Seq analysis, mRNA analysis, and DigiWest protein profiling were performed. Results: Tissue microarray analysis revealed higher ADORA3 expression in nonmalignant samples and a subset of tumors with weak or absent ADORA3 expression. This was supported by RNA sequencing data from The Cancer Genome Atlas and needle biopsy samples. Cell lines and PDOs exhibited antiproliferative effects with the ADORA3 agonist Namodenoson, confirmed by receptor dependency tests with specific antagonists and siRNA experiments. Genome-wide RNA-Seq analysis suggested chromatin remodeling events after ADORA3 stimulation. mRNA expression and DigiWest profiling identified downregulation of histone deacetylases and histone H3 modifications. Combination treatments with different ADORA3 agonists and histone deacetylase inhibitors significantly enhanced antiproliferative effects in almost all selected combinations, supported by investigations in PDOs. Conclusion: ADORA3 expression varies considerably in HCC or CCA, ranging from high to absent receptor detection. This observation might help to identify patients for clinical studies. Additionally, Namodenoson’s epigenetic modulating activity suggests epigenetic drugs as promising candidates for combination treatment. |
| format | Article |
| id | doaj-art-04138a83400b463a96fe8fdc3a680d64 |
| institution | OA Journals |
| issn | 2772-5723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Gastro Hep Advances |
| spelling | doaj-art-04138a83400b463a96fe8fdc3a680d642025-08-20T02:10:03ZengElsevierGastro Hep Advances2772-57232025-01-014310059010.1016/j.gastha.2024.11.006Adenosine Receptor 3 in Liver Cancer: Expression Variability, Epigenetic Modulation, and Enhanced Histone Deacetylase Inhibitor EffectsLouise Kaldjob-Heinrich0Sandro Nuciforo1Steffen Lemke2Aaron Stahl3Stefan Czemmel4Sepideh Babaei5Lauriane Blukacz6Marie-Anne Meier7Yizheng Zhang8Christian M. Schürch9Irene Gonzalez-Menendez10Pascal Woelffing11Nisar P. Malek12Veit Scheble13Sven Nahnsen14Manfred Claassen15Markus Templin16Hans Bösmüller17Markus H. Heim18Daniel Dauch19Michael Bitzer20Department Internal Medicine I, Eberhard-Karls University, Tuebingen, GermanyDepartment of Biomedicine, University Hospital and University of Basel, Basel, Switzerland; Clinic of Gastroenterology and Hepatology, Clarunis University Center for Gastrointestinal and Liver Diseases Basel, Basel, SwitzerlandQuantitative Biology Center (QBiC), Eberhard-Karls University, Tuebingen, Germany; M3-Research Center for Malignome, Metabolome and Microbiome, Eberhard-Karls University, Tuebingen, GermanyNMI, Natural and Medical Sciences Institute at the University of Tuebingen, Reutlingen, GermanyQuantitative Biology Center (QBiC), Eberhard-Karls University, Tuebingen, Germany; M3-Research Center for Malignome, Metabolome and Microbiome, Eberhard-Karls University, Tuebingen, GermanyDepartment Internal Medicine I, Eberhard-Karls University, Tuebingen, Germany; M3-Research Center for Malignome, Metabolome and Microbiome, Eberhard-Karls University, Tuebingen, GermanyDepartment of Biomedicine, University Hospital and University of Basel, Basel, SwitzerlandDepartment of Biomedicine, University Hospital and University of Basel, Basel, Switzerland; Clinic of Gastroenterology and Hepatology, Clarunis University Center for Gastrointestinal and Liver Diseases Basel, Basel, SwitzerlandDepartment of Pathology and Neuropathology, Eberhard Karls University, Tübingen, GermanyDepartment of Pathology and Neuropathology, Eberhard Karls University, Tübingen, Germany; iFIT Cluster of Excellence EXC 2180 ‘Image-Guided and Functionally Instructed Tumor Therapies’, Eberhard-Karls University, Tuebingen, GermanyDepartment of Pathology and Neuropathology, Eberhard Karls University, Tübingen, Germany; iFIT Cluster of Excellence EXC 2180 ‘Image-Guided and Functionally Instructed Tumor Therapies’, Eberhard-Karls University, Tuebingen, GermanyiFIT Cluster of Excellence EXC 2180 ‘Image-Guided and Functionally Instructed Tumor Therapies’, Eberhard-Karls University, Tuebingen, Germany; Department of Medical Oncology and Pneumology, Eberhard-Karls University, Tuebingen, GermanyDepartment Internal Medicine I, Eberhard-Karls University, Tuebingen, Germany; M3-Research Center for Malignome, Metabolome and Microbiome, Eberhard-Karls University, Tuebingen, Germany; iFIT Cluster of Excellence EXC 2180 ‘Image-Guided and Functionally Instructed Tumor Therapies’, Eberhard-Karls University, Tuebingen, Germany; Center for Personalized Medicine, Eberhard-Karls University, Tuebingen, GermanyDepartment Internal Medicine I, Eberhard-Karls University, Tuebingen, GermanyQuantitative Biology Center (QBiC), Eberhard-Karls University, Tuebingen, Germany; M3-Research Center for Malignome, Metabolome and Microbiome, Eberhard-Karls University, Tuebingen, GermanyDepartment Internal Medicine I, Eberhard-Karls University, Tuebingen, Germany; M3-Research Center for Malignome, Metabolome and Microbiome, Eberhard-Karls University, Tuebingen, Germany; Department of Computer Science, University of Tübingen, Tübingen, Germany; Machine Learning in Science, Excellence Cluster Machine Learning, University of Tübingen, Tübingen, GermanyNMI, Natural and Medical Sciences Institute at the University of Tuebingen, Reutlingen, GermanyDepartment of Pathology and Neuropathology, Eberhard Karls University, Tübingen, GermanyDepartment of Biomedicine, University Hospital and University of Basel, Basel, Switzerland; Clinic of Gastroenterology and Hepatology, Clarunis University Center for Gastrointestinal and Liver Diseases Basel, Basel, SwitzerlandiFIT Cluster of Excellence EXC 2180 ‘Image-Guided and Functionally Instructed Tumor Therapies’, Eberhard-Karls University, Tuebingen, Germany; Department of Medical Oncology and Pneumology, Eberhard-Karls University, Tuebingen, GermanyDepartment Internal Medicine I, Eberhard-Karls University, Tuebingen, Germany; M3-Research Center for Malignome, Metabolome and Microbiome, Eberhard-Karls University, Tuebingen, Germany; iFIT Cluster of Excellence EXC 2180 ‘Image-Guided and Functionally Instructed Tumor Therapies’, Eberhard-Karls University, Tuebingen, Germany; Center for Personalized Medicine, Eberhard-Karls University, Tuebingen, Germany; Correspondence: Address correspondence to: Michael Bitzer, MD, Department Internal Medicine I, Eberhard-Karls University, Otfried-Mueller-Str. 10, Tübingen D-72076, Germany.Background and Aims: Primary liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), has low response rates to existing treatments, highlighting the urgent need for novel treatment options. Adenosine A3 receptor (ADORA3) signaling has emerged as a potential target. Namodenoson, an ADORA3 agonist, has shown promise in early clinical trials for HCC. However, further data are required to clarify ADORA3 expression patterns in liver cancer, mechanisms of action, and the potential for combination therapies to inform patient selection for future clinical trials. Methods: Patient-derived tissue microarrays and RNA-sequencing were employed to investigate ADORA3 expression. Cellular responses to ADORA3 stimulation and combination treatments were studied in HCC and CCA cell lines and patient-derived organoids (PDOs). Genome-wide RNA-Seq analysis, mRNA analysis, and DigiWest protein profiling were performed. Results: Tissue microarray analysis revealed higher ADORA3 expression in nonmalignant samples and a subset of tumors with weak or absent ADORA3 expression. This was supported by RNA sequencing data from The Cancer Genome Atlas and needle biopsy samples. Cell lines and PDOs exhibited antiproliferative effects with the ADORA3 agonist Namodenoson, confirmed by receptor dependency tests with specific antagonists and siRNA experiments. Genome-wide RNA-Seq analysis suggested chromatin remodeling events after ADORA3 stimulation. mRNA expression and DigiWest profiling identified downregulation of histone deacetylases and histone H3 modifications. Combination treatments with different ADORA3 agonists and histone deacetylase inhibitors significantly enhanced antiproliferative effects in almost all selected combinations, supported by investigations in PDOs. Conclusion: ADORA3 expression varies considerably in HCC or CCA, ranging from high to absent receptor detection. This observation might help to identify patients for clinical studies. Additionally, Namodenoson’s epigenetic modulating activity suggests epigenetic drugs as promising candidates for combination treatment.http://www.sciencedirect.com/science/article/pii/S2772572324001869Adenosine Receptor 3Hepatocellular CarcinomaCholangiocarcinomaEpigeneticCancer Combination Therapy |
| spellingShingle | Louise Kaldjob-Heinrich Sandro Nuciforo Steffen Lemke Aaron Stahl Stefan Czemmel Sepideh Babaei Lauriane Blukacz Marie-Anne Meier Yizheng Zhang Christian M. Schürch Irene Gonzalez-Menendez Pascal Woelffing Nisar P. Malek Veit Scheble Sven Nahnsen Manfred Claassen Markus Templin Hans Bösmüller Markus H. Heim Daniel Dauch Michael Bitzer Adenosine Receptor 3 in Liver Cancer: Expression Variability, Epigenetic Modulation, and Enhanced Histone Deacetylase Inhibitor Effects Gastro Hep Advances Adenosine Receptor 3 Hepatocellular Carcinoma Cholangiocarcinoma Epigenetic Cancer Combination Therapy |
| title | Adenosine Receptor 3 in Liver Cancer: Expression Variability, Epigenetic Modulation, and Enhanced Histone Deacetylase Inhibitor Effects |
| title_full | Adenosine Receptor 3 in Liver Cancer: Expression Variability, Epigenetic Modulation, and Enhanced Histone Deacetylase Inhibitor Effects |
| title_fullStr | Adenosine Receptor 3 in Liver Cancer: Expression Variability, Epigenetic Modulation, and Enhanced Histone Deacetylase Inhibitor Effects |
| title_full_unstemmed | Adenosine Receptor 3 in Liver Cancer: Expression Variability, Epigenetic Modulation, and Enhanced Histone Deacetylase Inhibitor Effects |
| title_short | Adenosine Receptor 3 in Liver Cancer: Expression Variability, Epigenetic Modulation, and Enhanced Histone Deacetylase Inhibitor Effects |
| title_sort | adenosine receptor 3 in liver cancer expression variability epigenetic modulation and enhanced histone deacetylase inhibitor effects |
| topic | Adenosine Receptor 3 Hepatocellular Carcinoma Cholangiocarcinoma Epigenetic Cancer Combination Therapy |
| url | http://www.sciencedirect.com/science/article/pii/S2772572324001869 |
| work_keys_str_mv | AT louisekaldjobheinrich adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT sandronuciforo adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT steffenlemke adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT aaronstahl adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT stefanczemmel adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT sepidehbabaei adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT laurianeblukacz adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT marieannemeier adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT yizhengzhang adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT christianmschurch adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT irenegonzalezmenendez adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT pascalwoelffing adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT nisarpmalek adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT veitscheble adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT svennahnsen adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT manfredclaassen adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT markustemplin adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT hansbosmuller adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT markushheim adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT danieldauch adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects AT michaelbitzer adenosinereceptor3inlivercancerexpressionvariabilityepigeneticmodulationandenhancedhistonedeacetylaseinhibitoreffects |