2. Academic Validation
  3. Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation

Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation

  • Cancer Metab. 2025 Mar 31;13(1):16. doi: 10.1186/s40170-025-00382-6.
Anna Solta # 1,  Büsra Ernhofer # 1,  Kristiina Boettiger 1,  Christian Lang 1 2,  Zsolt Megyesfalvi 1 3 4,  Theresa Mendrina 5 6,  Dominik Kirchhofer 5,  Gerald Timelthaler 5,  Beata Szeitz 4,  Melinda Rezeli 7,  Clemens Aigner 1,  Arvand Haschemi 8,  Lukas W Unger 9 10,  Balazs Dome 11 12 13 14,  Karin Schelch 15 16
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, A-1090, Austria.
  • 2 Division of Pulmonology, Department of Medicine II, Medical University of Vienna, Vienna, Austria.
  • 3 Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary.
  • 4 National Koranyi Institute of Pulmonology, Budapest, Hungary.
  • 5 Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
  • 6 Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
  • 7 Department of Biomedical Engineering, Lund University, Lund, Sweden.
  • 8 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
  • 9 Deptartment of Colorectal Surgery, Oxford University Hospitals, Oxford, UK.
  • 10 Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria.
  • 11 Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, A-1090, Austria. balazs.dome@meduniwien.ac.at.
  • 12 Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary. balazs.dome@meduniwien.ac.at.
  • 13 National Koranyi Institute of Pulmonology, Budapest, Hungary. balazs.dome@meduniwien.ac.at.
  • 14 Department of Translational Medicine, Lund University, Lund, Sweden. balazs.dome@meduniwien.ac.at.
  • 15 Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, A-1090, Austria. karin.schelch@meduniwien.ac.at.
  • 16 Center for Cancer Research, Medical University of Vienna, Vienna, Austria. karin.schelch@meduniwien.ac.at.
  • # Contributed equally.
PMID: 40165271 DOI: 10.1186/s40170-025-00382-6
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.

Keywords

Metabolism; Molecular subtypes; Oxidative phosphorylation; Small cell lung cancer.

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