Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation
Abstract Background Small cell lung cancer (SCLC) is an aggressive malignancy with distinct molecular subtypes defined by transcription factors and inflammatory characteristics. This follow-up study aimed to validate the unique metabolic phenotype in achaete-scute homologue 1 (ASCL1)-driven SCLC cel...
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BMC
2025-03-01
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| Series: | Cancer & Metabolism |
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| Online Access: | https://doi.org/10.1186/s40170-025-00382-6 |
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| author | Anna Solta Büsra Ernhofer Kristiina Boettiger Christian Lang Zsolt Megyesfalvi Theresa Mendrina Dominik Kirchhofer Gerald Timelthaler Beata Szeitz Melinda Rezeli Clemens Aigner Arvand Haschemi Lukas W. Unger Balazs Dome Karin Schelch |
| author_facet | Anna Solta Büsra Ernhofer Kristiina Boettiger Christian Lang Zsolt Megyesfalvi Theresa Mendrina Dominik Kirchhofer Gerald Timelthaler Beata Szeitz Melinda Rezeli Clemens Aigner Arvand Haschemi Lukas W. Unger Balazs Dome Karin Schelch |
| author_sort | Anna Solta |
| collection | DOAJ |
| description | Abstract Background Small cell lung cancer (SCLC) is an aggressive malignancy with distinct molecular subtypes defined by transcription factors and inflammatory characteristics. This follow-up study aimed to validate the unique metabolic phenotype in achaete-scute homologue 1 (ASCL1)-driven SCLC cell lines and human tumor tissue. Methods Metabolic alterations were analyzed using proteomic data. Structural and functional differences of mitochondria were investigated using qPCR, flow cytometry, confocal imaging, and transmission electron microscopy and seahorse assays. Several metabolic inhibitors were tested using MTT-based and clonogenic assays. Single-cell enzyme activity assays were conducted on cell lines and tumor tissue samples of SCLC patients. Results We found increased mitochondrial numbers correlating with higher oxidative phosphorylation activity in ASCL1-dominant cells compared to other SCLC subtypes. Metabolic inhibitors targeting mitochondrial respiratory complex-I or carnitine palmitoyltransferase 1 revealed higher responsiveness in SCLC-A. Conversely, we demonstrated that non-ASCL1-driven SCLCs with lower oxidative signatures show dependence on glutaminolysis as evidenced by the enhanced susceptibility to glutaminase inhibition. Accordingly, we detected increased glutamate-dehydrogenase activity in non-ASCL1-dominant cell lines as well as in human SCLC tissue samples. Conclusions Distinct SCLC subtypes exhibit unique metabolic vulnerabilities, suggesting potential for subtype-specific therapies targeting the respiratory chain, fatty acid transport, or glutaminolysis. Graphical abstract |
| format | Article |
| id | doaj-art-0397f4677dbf47df831eaf26c9ba92f8 |
| institution | OA Journals |
| issn | 2049-3002 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer & Metabolism |
| spelling | doaj-art-0397f4677dbf47df831eaf26c9ba92f82025-08-20T02:25:41ZengBMCCancer & Metabolism2049-30022025-03-0113111910.1186/s40170-025-00382-6Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylationAnna Solta0Büsra Ernhofer1Kristiina Boettiger2Christian Lang3Zsolt Megyesfalvi4Theresa Mendrina5Dominik Kirchhofer6Gerald Timelthaler7Beata Szeitz8Melinda Rezeli9Clemens Aigner10Arvand Haschemi11Lukas W. Unger12Balazs Dome13Karin Schelch14Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of ViennaDepartment of Thoracic Surgery, Comprehensive Cancer Center, Medical University of ViennaDepartment of Thoracic Surgery, Comprehensive Cancer Center, Medical University of ViennaDepartment of Thoracic Surgery, Comprehensive Cancer Center, Medical University of ViennaDepartment of Thoracic Surgery, Comprehensive Cancer Center, Medical University of ViennaCenter for Cancer Research, Medical University of ViennaCenter for Cancer Research, Medical University of ViennaCenter for Cancer Research, Medical University of ViennaNational Koranyi Institute of PulmonologyDepartment of Biomedical Engineering, Lund UniversityDepartment of Thoracic Surgery, Comprehensive Cancer Center, Medical University of ViennaDepartment of Laboratory Medicine, Medical University of ViennaDeptartment of Colorectal Surgery, Oxford University HospitalsDepartment of Thoracic Surgery, Comprehensive Cancer Center, Medical University of ViennaDepartment of Thoracic Surgery, Comprehensive Cancer Center, Medical University of ViennaAbstract Background Small cell lung cancer (SCLC) is an aggressive malignancy with distinct molecular subtypes defined by transcription factors and inflammatory characteristics. This follow-up study aimed to validate the unique metabolic phenotype in achaete-scute homologue 1 (ASCL1)-driven SCLC cell lines and human tumor tissue. Methods Metabolic alterations were analyzed using proteomic data. Structural and functional differences of mitochondria were investigated using qPCR, flow cytometry, confocal imaging, and transmission electron microscopy and seahorse assays. Several metabolic inhibitors were tested using MTT-based and clonogenic assays. Single-cell enzyme activity assays were conducted on cell lines and tumor tissue samples of SCLC patients. Results We found increased mitochondrial numbers correlating with higher oxidative phosphorylation activity in ASCL1-dominant cells compared to other SCLC subtypes. Metabolic inhibitors targeting mitochondrial respiratory complex-I or carnitine palmitoyltransferase 1 revealed higher responsiveness in SCLC-A. Conversely, we demonstrated that non-ASCL1-driven SCLCs with lower oxidative signatures show dependence on glutaminolysis as evidenced by the enhanced susceptibility to glutaminase inhibition. Accordingly, we detected increased glutamate-dehydrogenase activity in non-ASCL1-dominant cell lines as well as in human SCLC tissue samples. Conclusions Distinct SCLC subtypes exhibit unique metabolic vulnerabilities, suggesting potential for subtype-specific therapies targeting the respiratory chain, fatty acid transport, or glutaminolysis. Graphical abstracthttps://doi.org/10.1186/s40170-025-00382-6Small cell lung cancerMetabolismOxidative phosphorylationMolecular subtypes |
| spellingShingle | Anna Solta Büsra Ernhofer Kristiina Boettiger Christian Lang Zsolt Megyesfalvi Theresa Mendrina Dominik Kirchhofer Gerald Timelthaler Beata Szeitz Melinda Rezeli Clemens Aigner Arvand Haschemi Lukas W. Unger Balazs Dome Karin Schelch Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation Cancer & Metabolism Small cell lung cancer Metabolism Oxidative phosphorylation Molecular subtypes |
| title | Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation |
| title_full | Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation |
| title_fullStr | Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation |
| title_full_unstemmed | Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation |
| title_short | Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation |
| title_sort | unveiling the powerhouse ascl1 driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation |
| topic | Small cell lung cancer Metabolism Oxidative phosphorylation Molecular subtypes |
| url | https://doi.org/10.1186/s40170-025-00382-6 |
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