A patient-derived HCC spheroid system to model the tumor microenvironment and treatment response
Background & Aims: Hepatocellular carcinoma (HCC) is the third-leading and fastest rising cause of cancer-related death worldwide. The discovery and preclinical development of compounds targeting HCC are hampered by the absence of authentic tractable systems recapitulating the heterogeneity...
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Elsevier
2025-02-01
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| author | Emilie Crouchet Nuno Almeida Sarah C. Durand Marie Parnot Marine A. Oudot Fabio Giannone Cloé Gadenne Natascha Roehlen Antonio Saviano Emanuele Felli Patrick Pessaux Hong Tuan Duong Hideki Ohdan Hiroshi Aikata Kazuaki Chayama Thomas F. Baumert Catherine Schuster |
| author_facet | Emilie Crouchet Nuno Almeida Sarah C. Durand Marie Parnot Marine A. Oudot Fabio Giannone Cloé Gadenne Natascha Roehlen Antonio Saviano Emanuele Felli Patrick Pessaux Hong Tuan Duong Hideki Ohdan Hiroshi Aikata Kazuaki Chayama Thomas F. Baumert Catherine Schuster |
| author_sort | Emilie Crouchet |
| collection | DOAJ |
| description | Background & Aims: Hepatocellular carcinoma (HCC) is the third-leading and fastest rising cause of cancer-related death worldwide. The discovery and preclinical development of compounds targeting HCC are hampered by the absence of authentic tractable systems recapitulating the heterogeneity of HCC tumors in patients and the tumor microenvironment (TME). Methods: We established a novel and simple patient-derived multicellular tumor spheroid model based on clinical HCC tumor tissues, processed using enzymatic and mechanical dissociation. After quality controls, 22 HCC tissues and 17 HCC sera were selected for tumor spheroid generation and perturbation studies. Cells were grown in 3D in optimized medium in the presence of patient serum. Characterization of the tumor spheroid cell populations was performed by flow cytometry, immunohistochemistry (IHC), and functional assays. As a proof of concept, we treated patient-derived spheroids with FDA-approved anti-HCC compounds. Results: The model was successfully established independently from cancer etiology and grade from 22 HCC tissues. The use of serum from patients with HCC was essential for tumor spheroid generation, TME function, and maintenance of cell viability. The tumor spheroids comprised the main cell compartments, including epithelial cancer cells, as well as all major cell populations of the TME [i.e. cancer-associated fibroblasts (CAFs), macrophages, T cells, and endothelial cells]. Tumor spheroids reflected HCC heterogeneity, including variability in cell type proportions and TME, and mimicked the original tumor features. Moreover, differential responses to FDA-approved anti-HCC drugs were observed between the donors, as observed in patients. Conclusions: This patient HCC serum-tumor spheroid model provides novel opportunities for drug discovery and development as well as mechanism-of-action studies including compounds targeting the TME. This model will likely contribute to improve the therapeutic outcomes for patients with HCC. Impact and implications:: HCC is a leading and fast-rising cause of cancer-related death worldwide. Despite approval of novel therapies, the outcome of advanced HCC remains unsatisfactory. By developing a novel patient-derived tumor spheroid model recapitulating tumor heterogeneity and microenvironment, we provide new opportunities for HCC drug development and analysis of mechanism of action in authentic patient tissues. The application of the patient-derived tumor spheroids combined with other HCC models will likely contribute to drug development and to improve the outcome of patients with HCC. |
| format | Article |
| id | doaj-art-cdff5a0b71e44a159c27b202d782ffd0 |
| institution | Kabale University |
| issn | 2589-5559 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
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| series | JHEP Reports |
| spelling | doaj-art-cdff5a0b71e44a159c27b202d782ffd02025-02-07T04:48:08ZengElsevierJHEP Reports2589-55592025-02-0172101252A patient-derived HCC spheroid system to model the tumor microenvironment and treatment responseEmilie Crouchet0Nuno Almeida1Sarah C. Durand2Marie Parnot3Marine A. Oudot4Fabio Giannone5Cloé Gadenne6Natascha Roehlen7Antonio Saviano8Emanuele Felli9Patrick Pessaux10Hong Tuan Duong11Hideki Ohdan12Hiroshi Aikata13Kazuaki Chayama14Thomas F. Baumert15Catherine Schuster16University of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease UMR S1110, Strasbourg, France; Corresponding authors. Address: Inserm U1110, University of Strasbourg. 3 rue Koeberlé, 67000 Strasbourg, France. Tel.: +33368853703 (T.F. Baumert); Tel.: +33368853741 (C. Schuster); Tel.: +33368853626 (E. Crouchet).University of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease UMR S1110, Strasbourg, FranceUniversity of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease UMR S1110, Strasbourg, FranceUniversity of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease UMR S1110, Strasbourg, FranceUniversity of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease UMR S1110, Strasbourg, FranceUniversity of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease UMR S1110, Strasbourg, France; Hepato-Pancreato-Biliary, Oncologic and Robotic Unit, Azienda Ospedaliero-Universitaria SS, Antonio e Biagio e Cesare Arrigo, Alessandria, ItalyUniversity of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease UMR S1110, Strasbourg, FranceUniversity of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease UMR S1110, Strasbourg, FranceUniversity of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease UMR S1110, Strasbourg, France; Gastroenterology and Hepatology Service, Strasbourg University Hospitals, Strasbourg, FranceUniversity of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease UMR S1110, Strasbourg, France; Hospital Group Saint Vincent, Strasbourg, FranceUniversity of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease UMR S1110, Strasbourg, France; Department of Visceral and Digestive Surgery, University Hospital of Strasbourg, Strasbourg, FranceUniversity of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease UMR S1110, Strasbourg, FranceDepartment of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, JapanDepartment of Gastroenterology and Hepatology, Hiroshima Prefectural Hospital, Hiroshima, JapanHiroshima Institute of Life Sciences, Hiroshima, Japan; RIKEN Center for Integrative Medical Sciences, Yokohama, JapanUniversity of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease UMR S1110, Strasbourg, France; Gastroenterology and Hepatology Service, Strasbourg University Hospitals, Strasbourg, France; Department of Visceral and Digestive Surgery, University Hospital of Strasbourg, Strasbourg, France; Institut Universitaire de France (IUF), Paris, France; Corresponding authors. Address: Inserm U1110, University of Strasbourg. 3 rue Koeberlé, 67000 Strasbourg, France. Tel.: +33368853703 (T.F. Baumert); Tel.: +33368853741 (C. Schuster); Tel.: +33368853626 (E. Crouchet).University of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease UMR S1110, Strasbourg, France; Corresponding authors. Address: Inserm U1110, University of Strasbourg. 3 rue Koeberlé, 67000 Strasbourg, France. Tel.: +33368853703 (T.F. Baumert); Tel.: +33368853741 (C. Schuster); Tel.: +33368853626 (E. Crouchet).Background & Aims: Hepatocellular carcinoma (HCC) is the third-leading and fastest rising cause of cancer-related death worldwide. The discovery and preclinical development of compounds targeting HCC are hampered by the absence of authentic tractable systems recapitulating the heterogeneity of HCC tumors in patients and the tumor microenvironment (TME). Methods: We established a novel and simple patient-derived multicellular tumor spheroid model based on clinical HCC tumor tissues, processed using enzymatic and mechanical dissociation. After quality controls, 22 HCC tissues and 17 HCC sera were selected for tumor spheroid generation and perturbation studies. Cells were grown in 3D in optimized medium in the presence of patient serum. Characterization of the tumor spheroid cell populations was performed by flow cytometry, immunohistochemistry (IHC), and functional assays. As a proof of concept, we treated patient-derived spheroids with FDA-approved anti-HCC compounds. Results: The model was successfully established independently from cancer etiology and grade from 22 HCC tissues. The use of serum from patients with HCC was essential for tumor spheroid generation, TME function, and maintenance of cell viability. The tumor spheroids comprised the main cell compartments, including epithelial cancer cells, as well as all major cell populations of the TME [i.e. cancer-associated fibroblasts (CAFs), macrophages, T cells, and endothelial cells]. Tumor spheroids reflected HCC heterogeneity, including variability in cell type proportions and TME, and mimicked the original tumor features. Moreover, differential responses to FDA-approved anti-HCC drugs were observed between the donors, as observed in patients. Conclusions: This patient HCC serum-tumor spheroid model provides novel opportunities for drug discovery and development as well as mechanism-of-action studies including compounds targeting the TME. This model will likely contribute to improve the therapeutic outcomes for patients with HCC. Impact and implications:: HCC is a leading and fast-rising cause of cancer-related death worldwide. Despite approval of novel therapies, the outcome of advanced HCC remains unsatisfactory. By developing a novel patient-derived tumor spheroid model recapitulating tumor heterogeneity and microenvironment, we provide new opportunities for HCC drug development and analysis of mechanism of action in authentic patient tissues. The application of the patient-derived tumor spheroids combined with other HCC models will likely contribute to drug development and to improve the outcome of patients with HCC.http://www.sciencedirect.com/science/article/pii/S2589555924002568Liver cancer3D modelTumor spheroidsDrug discovery and developmentImmuno-oncology |
| spellingShingle | Emilie Crouchet Nuno Almeida Sarah C. Durand Marie Parnot Marine A. Oudot Fabio Giannone Cloé Gadenne Natascha Roehlen Antonio Saviano Emanuele Felli Patrick Pessaux Hong Tuan Duong Hideki Ohdan Hiroshi Aikata Kazuaki Chayama Thomas F. Baumert Catherine Schuster A patient-derived HCC spheroid system to model the tumor microenvironment and treatment response JHEP Reports Liver cancer 3D model Tumor spheroids Drug discovery and development Immuno-oncology |
| title | A patient-derived HCC spheroid system to model the tumor microenvironment and treatment response |
| title_full | A patient-derived HCC spheroid system to model the tumor microenvironment and treatment response |
| title_fullStr | A patient-derived HCC spheroid system to model the tumor microenvironment and treatment response |
| title_full_unstemmed | A patient-derived HCC spheroid system to model the tumor microenvironment and treatment response |
| title_short | A patient-derived HCC spheroid system to model the tumor microenvironment and treatment response |
| title_sort | patient derived hcc spheroid system to model the tumor microenvironment and treatment response |
| topic | Liver cancer 3D model Tumor spheroids Drug discovery and development Immuno-oncology |
| url | http://www.sciencedirect.com/science/article/pii/S2589555924002568 |
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