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

Author(s)

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

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.

Organisation(s)

Department of Inorganic Chemistry

External organisation(s)

Medizinische Universität Wien, National Korányi Institute of Pulmonology, Lund University

Journal

Cancer & metabolism

Volume

13

ISSN

2049-3002

DOI

https://doi.org/10.1186/s40170-025-00382-6

Publication date

03-2025

Peer reviewed

Yes

Austrian Fields of Science 2012

301904 Cancer research

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Portal url

https://ucrisportal.univie.ac.at/en/publications/a5a848d8-7588-4220-88ed-55baea396bdd