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Kabiljo J, Theophil A, Homola J, Renner AF, Stürzenbecher N, Ammon D, Zirnbauer R, Stang S, Tran L, Laengle J, Kulu A, Chen A, Fabits M, Atanasova VS, Pusch O, Weninger W, Walczak H, Herndler Brandstetter D, Egger G, Dolznig H, Kusienicka A, Farlik M, Bergmann M. Cancer-associated fibroblasts shape early myeloid cell response to chemotherapy-induced immunogenic signals in next generation tumor organoid cultures. J Immunother Cancer 2024; 12:e009494. [PMID: 39500527 PMCID: PMC11535717 DOI: 10.1136/jitc-2024-009494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/26/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND Patient-derived colorectal cancer (CRC) organoids (PDOs) solely consisting of malignant cells led to major advances in the understanding of cancer treatments. Yet, a major limitation is the absence of cells from the tumor microenvironment, thereby prohibiting potential investigation of treatment responses on immune and structural cells. Currently there are sparse reports describing the interaction of PDOs, cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) in complex primary co-culture assay systems. METHODS Primary PDOs and patient matched CAF cultures were generated from surgical resections. Co-culture systems of PDOs, CAFs and monocytic myeloid cells were set up to recapitulate features seen in patient tumors. Single-cell transcriptomics and flow cytometry was used to show effects of culture systems on TAM populations in the co-culture assays under chemotherapeutic and oncolytic viral treatment. RESULTS In contrast to co-cultures of tumor cells and monocytes, CAF/monocyte co-cultures and CAF/monocyte/tumor cell triple cultures resulted in a partial differentiation into macrophages and a phenotypic switch, characterized by the expression of major immunosuppressive markers comparable to TAMs in CRC. Oxaliplatin and 5-fluorouracil, the standard-of-care chemotherapy for CRC, induced polarization of macrophages to a pro-inflammatory phenotype comparable to the immunogenic effects of treatment with an oncolytic virus. Monitoring phagocytosis as a functional proxy to macrophage activation and subsequent onset of an immune response, revealed that chemotherapy-induced cell death, but not virus-mediated cell death, is necessary to induce phagocytosis of CRC cells. Moreover, CAFs enhanced the phagocytic activity in chemotherapy treated CRC triple cultures. CONCLUSIONS Primary CAF-containing triple cultures successfully model TAM-like phenotypes ex vivo and allow the assessment of their functional and phenotypic changes in response to treatments following a precision medicine approach.
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Affiliation(s)
- Julijan Kabiljo
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
- Ludwig Boltzmann Institute Applied Diagnostics, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Anna Theophil
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
- Ludwig Boltzmann Institute Applied Diagnostics, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Jakob Homola
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Annalena F Renner
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Nathalie Stürzenbecher
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Daphni Ammon
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Rebecca Zirnbauer
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Simone Stang
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
| | - Loan Tran
- Ludwig Boltzmann Institute Applied Diagnostics, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Johannes Laengle
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
- Ludwig Boltzmann Institute Applied Diagnostics, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Askin Kulu
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Anna Chen
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Markus Fabits
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Velina S Atanasova
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
| | - Oliver Pusch
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Wolfgang Weninger
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Henning Walczak
- Institute for Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany
- Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK
| | - Dietmar Herndler Brandstetter
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Gerda Egger
- Ludwig Boltzmann Institute Applied Diagnostics, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Helmut Dolznig
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
| | - Anna Kusienicka
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Matthias Farlik
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Michael Bergmann
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
- Ludwig Boltzmann Institute Applied Diagnostics, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
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Yu QX, Fu PY, Zhang C, Li L, Huang WT. Mesenchymal-epithelial transition factor amplification correlates with adverse pathological features and poor clinical outcome in colorectal cancer. World J Gastrointest Surg 2024; 16:1395-1406. [PMID: 38817281 PMCID: PMC11135301 DOI: 10.4240/wjgs.v16.i5.1395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 02/22/2024] [Accepted: 04/11/2024] [Indexed: 05/23/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related mortality worldwide. Mesenchymal-epithelial transition factor (MET) gene participates in multiple tumor biology and shows clinical potential for pharmacological manipulation in tumor treatment. MET amplification has been reported in CRC, but data are very limited. Investigating pathological values of MET in CRC may provide new therapeutic and genetic screening options in future clinical practice. AIM To determine the pathological significance of MET amplification in CRC and to propose a feasible screening strategy. METHODS A number of 205 newly diagnosed CRC patients undergoing surgical resection without any preoperative therapy at Shenzhen Cancer Hospital of Chinese Academy of Medical Sciences were recruited. All patients were without RAS/RAF mutation or microsatellite instability-high. MET amplification and c-MET protein expression were analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively. Correlations between MET aberration and pathological features were detected using the chi-squared test. Progression free survival (PFS) during the two-year follow-up was detected using the Kaplan-Meier method and log rank test. The results of MET FISH and IHC were compared using one-way ANOVA. RESULTS Polysomy-induced MET amplification was observed in 14.4% of cases, and focal MET amplification was not detected. Polysomy-induced MET amplification was associated with a higher frequency of lymph node metastasis (LNM) (P < 0.001) and higher tumor budding grade (P = 0.02). In the survival analysis, significant difference was detected between patients with amplified- and non-amplified MET in a two-year follow-up after the first diagnosis (P = 0.001). C-MET scores of 0, 1+, 2+, and 3+ were observed in 1.4%, 24.9%, 54.7%, and 19.0% of tumors, respectively. C-MET overexpression correlated with higher frequency of LNM (P = 0.002), but no significant difference of PFS was detected between patients with different protein levels. In terms of concordance between MET FISH and IHC results, MET copy number showed no difference in c-MET IHC 0/1+ (3.35 ± 0.18), 2+ (3.29 ± 0.11) and 3+ (3.58 ± 0.22) cohorts, and the MET-to-CEP7 ratio showed no difference in three groups (1.09 ± 0.02, 1.10 ± 0.01, and 1.09 ± 0.03). CONCLUSION In CRC, focal MET amplification was a rare event. Polysomy-induced MET amplification correlated with adverse pathological characteristics and poor prognosis. IHC was a poor screening tool for MET amplification.
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Affiliation(s)
- Qiu-Xiao Yu
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, Guangdong Province, China
| | - Ping-Ying Fu
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, Guangdong Province, China
| | - Chi Zhang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, Guangdong Province, China
| | - Li Li
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, Guangdong Province, China
| | - Wen-Ting Huang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, Guangdong Province, China
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Zhang Z, Li D, Yun H, Tong J, Liu W, Chai K, Zeng T, Gao Z, Xie Y. Opportunities and challenges of targeting c-Met in the treatment of digestive tumors. Front Oncol 2022; 12:923260. [PMID: 35978812 PMCID: PMC9376446 DOI: 10.3389/fonc.2022.923260] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
At present, a large number of studies have demonstrated that c-Met generally exerts a crucial function of promoting tumor cells proliferation and differentiation in digestive system tumors. c-Met also mediates tumor progression and drug resistance by signaling interactions with other oncogenic molecules and then activating downstream pathways. Therefore, c-Met is a promising target for the treatment of digestive system tumors. Many anti-tumor therapies targeting c-Met (tyrosine kinase inhibitors, monoclonal antibodies, and adoptive immunotherapy) have been developed in treating digestive system tumors. Some drugs have been successfully applied to clinic, but most of them are defective due to their efficacy and complications. In order to promote the clinical application of targeting c-Met drugs in digestive system tumors, it is necessary to further explore the mechanism of c-Met action in digestive system tumors and optimize the anti-tumor treatment of targeting c-Met drugs. Through reading a large number of literatures, the author systematically reviewed the biological functions and molecular mechanisms of c-Met associated with tumor and summarized the current status of targeting c-Met in the treatment of digestive system tumors so as to provide new ideas for the treatment of digestive system tumors.
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Affiliation(s)
- Zhengchao Zhang
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China
| | - Dong Li
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Heng Yun
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Jie Tong
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Wei Liu
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Keqiang Chai
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Tongwei Zeng
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
| | - Zhenghua Gao
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
- *Correspondence: Yongqiang Xie, ; Zhenghua Gao,
| | - Yongqiang Xie
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Baiyin, China
- *Correspondence: Yongqiang Xie, ; Zhenghua Gao,
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