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

Solta, Anna and Ernhofer, Büsra and Boettiger, Kristiina and Lang, Christian and Megyesfalvi, Zsolt and Mendrina, Theresa and Kirchhofer, Dominik and Timelthaler, Gerald and Szeitz, Beáta and Rezeli, Melinda and Aigner, Clemens and Haschemi, Arvand and Unger, Lukas W. and Döme, Balázs and Schelch, Karin (2025) Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation. CANCER & METABOLISM, 13 (1). No. 16. ISSN 2049-3002

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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 subtypespecific therapies targeting the respiratory chain, fatty acid transport, or glutaminolysis.

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