Metabolomic and transcriptomic response to imatinib treatment of gastrointestinal stromal tumour in xenograft-bearing mice
Background: Although imatinib is a well-established first-line drug for treating a vast majority of gastrointestinal stromal tumours (GIST), GISTs acquire secondary resistance during therapy. Multi-omics approaches provide an integrated perspective to empower the development of personalised therapie...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | Translational Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523323000189 |
| _version_ | 1828012095746080768 |
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| author | Szymon Macioszek Danuta Dudzik Rafał Bartoszewski Tomasz Stokowy Diether Lambrechts Bram Boeckx Agnieszka Wozniak Patrick Schöffski Michał J. Markuszewski |
| author_facet | Szymon Macioszek Danuta Dudzik Rafał Bartoszewski Tomasz Stokowy Diether Lambrechts Bram Boeckx Agnieszka Wozniak Patrick Schöffski Michał J. Markuszewski |
| author_sort | Szymon Macioszek |
| collection | DOAJ |
| description | Background: Although imatinib is a well-established first-line drug for treating a vast majority of gastrointestinal stromal tumours (GIST), GISTs acquire secondary resistance during therapy. Multi-omics approaches provide an integrated perspective to empower the development of personalised therapies through a better understanding of functional biology underlying the disease and molecular-driven selection of the best-targeted individualised therapy. In this study, we applied integrative metabolomic and transcriptomic analyses to elucidate tumour biochemical processes affected by imatinib treatment. Materials and methods: A GIST xenograft mouse model was used in the study, including 10 mice treated with imatinib and 10 non-treated controls. Metabolites in tumour extracts were analysed using gas chromatography coupled with mass spectrometry (GC-MS). RNA sequencing was also performed on the samples subset (n=6). Results: Metabolomic analysis revealed 21 differentiating metabolites, whereas next-generation RNA sequencing data analysis resulted in 531 differentially expressed genes. Imatinib significantly changed the profile of metabolites associated mainly with purine and pyrimidine metabolism, butanoate metabolism, as well as alanine, aspartate, and glutamate metabolism. The related changes in transcriptomic profiles included genes involved in kinase activity and immune responses, as well as supported its impact on the purine biosynthesis pathway. Conclusions: Our multi-omics study confirmed previously known pathways involved in imatinib anticancer activity as well as correlated imatinib-relevant downregulation of expression of purine biosynthesis pathway genes with the reduction of respectful metabolites. Furthermore, considering the importance of the purine biosynthesis pathway for cancer proliferation, we identified a potentially novel mechanism for the anti-tumour activity of imatinib. Based on the results, we hypothesise metabolic modulations aiming at the reduction in purine and pyrimidine pool may ensure higher imatinib efficacy or re-sensitise imatinib-resistant tumours. |
| first_indexed | 2024-04-10T09:25:16Z |
| format | Article |
| id | doaj.art-45e412c3a749489d854a7e0c278adf19 |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-04-10T09:25:16Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-45e412c3a749489d854a7e0c278adf192023-02-20T04:08:59ZengElsevierTranslational Oncology1936-52332023-04-0130101632Metabolomic and transcriptomic response to imatinib treatment of gastrointestinal stromal tumour in xenograft-bearing miceSzymon Macioszek0Danuta Dudzik1Rafał Bartoszewski2Tomasz Stokowy3Diether Lambrechts4Bram Boeckx5Agnieszka Wozniak6Patrick Schöffski7Michał J. Markuszewski8Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Hallera 107, 80-416 Gdańsk, PolandDepartment of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Hallera 107, 80-416 Gdańsk, PolandDepartment of Biophysics, Faculty of Biotechnology, University of Wrocław, F. Joliot-Curie 14a Street, 50-383 Wrocław, PolandIT Division, University of Bergen, 5021, Bergen, NorwayLaboratory of Translational Genetics, KU Leuven and VIB Center for Cancer Biology, Leuven, BelgiumLaboratory of Translational Genetics, KU Leuven and VIB Center for Cancer Biology, Leuven, BelgiumLaboratory of Experimental Oncology, Department of Oncology, KU Leuven, and Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, BelgiumLaboratory of Experimental Oncology, Department of Oncology, KU Leuven, and Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, BelgiumDepartment of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Hallera 107, 80-416 Gdańsk, Poland; Corresponding author.Background: Although imatinib is a well-established first-line drug for treating a vast majority of gastrointestinal stromal tumours (GIST), GISTs acquire secondary resistance during therapy. Multi-omics approaches provide an integrated perspective to empower the development of personalised therapies through a better understanding of functional biology underlying the disease and molecular-driven selection of the best-targeted individualised therapy. In this study, we applied integrative metabolomic and transcriptomic analyses to elucidate tumour biochemical processes affected by imatinib treatment. Materials and methods: A GIST xenograft mouse model was used in the study, including 10 mice treated with imatinib and 10 non-treated controls. Metabolites in tumour extracts were analysed using gas chromatography coupled with mass spectrometry (GC-MS). RNA sequencing was also performed on the samples subset (n=6). Results: Metabolomic analysis revealed 21 differentiating metabolites, whereas next-generation RNA sequencing data analysis resulted in 531 differentially expressed genes. Imatinib significantly changed the profile of metabolites associated mainly with purine and pyrimidine metabolism, butanoate metabolism, as well as alanine, aspartate, and glutamate metabolism. The related changes in transcriptomic profiles included genes involved in kinase activity and immune responses, as well as supported its impact on the purine biosynthesis pathway. Conclusions: Our multi-omics study confirmed previously known pathways involved in imatinib anticancer activity as well as correlated imatinib-relevant downregulation of expression of purine biosynthesis pathway genes with the reduction of respectful metabolites. Furthermore, considering the importance of the purine biosynthesis pathway for cancer proliferation, we identified a potentially novel mechanism for the anti-tumour activity of imatinib. Based on the results, we hypothesise metabolic modulations aiming at the reduction in purine and pyrimidine pool may ensure higher imatinib efficacy or re-sensitise imatinib-resistant tumours.http://www.sciencedirect.com/science/article/pii/S1936523323000189MetabolomicsTranscriptomicsImatinibGISTpurinesMulti-omics |
| spellingShingle | Szymon Macioszek Danuta Dudzik Rafał Bartoszewski Tomasz Stokowy Diether Lambrechts Bram Boeckx Agnieszka Wozniak Patrick Schöffski Michał J. Markuszewski Metabolomic and transcriptomic response to imatinib treatment of gastrointestinal stromal tumour in xenograft-bearing mice Translational Oncology Metabolomics Transcriptomics Imatinib GIST purines Multi-omics |
| title | Metabolomic and transcriptomic response to imatinib treatment of gastrointestinal stromal tumour in xenograft-bearing mice |
| title_full | Metabolomic and transcriptomic response to imatinib treatment of gastrointestinal stromal tumour in xenograft-bearing mice |
| title_fullStr | Metabolomic and transcriptomic response to imatinib treatment of gastrointestinal stromal tumour in xenograft-bearing mice |
| title_full_unstemmed | Metabolomic and transcriptomic response to imatinib treatment of gastrointestinal stromal tumour in xenograft-bearing mice |
| title_short | Metabolomic and transcriptomic response to imatinib treatment of gastrointestinal stromal tumour in xenograft-bearing mice |
| title_sort | metabolomic and transcriptomic response to imatinib treatment of gastrointestinal stromal tumour in xenograft bearing mice |
| topic | Metabolomics Transcriptomics Imatinib GIST purines Multi-omics |
| url | http://www.sciencedirect.com/science/article/pii/S1936523323000189 |
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