bims-necame 2025-04-06 papers

Issue of 2025–04–06
two papers selected by
Grigor Varuzhanyan, UCLA

Cancer Metab. 2025 Mar 31. 13(1): 16

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

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.

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

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

J Cancer Res Clin Oncol. 2025 Mar 28. 151(3): 126

Increasing cisplatin exposure promotes small-cell lung cancer transformation after a shift from glucose metabolism to fatty acid metabolism.

Qiu-Yu Zhao, Wen-Jun Liu, Jian-Guang Wang, He Li, Jia-Lu Lv, Yumeng Wang, Chun Wang.

OBJECTIVES: Lung cancer is a leading cause of global cancer mortality. Clinical observations reveal that histological transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is accompanied by mutations in TP53 and RB1. By applying gradually increasing cisplatin concentrations to mimic the escalating drug pressure within the tumor microenvironment, this study investigated the link between phenotypic transformation to SCLC in cisplatin-resistant human lung adenocarcinoma cells and alterations in cellular energy production pathways.
MATERIALS AND METHODS: We established two cisplatin-resistant NSCLC cell lines with varying resistance levels. RNAseq analyses identified TP53 and RB1 gene mutations. Comprehensive functional assays were performed to characterize A549/DDP1 μg/mL and A549/DDP3 μg/mL cells, focusing on proliferation and migratory capabilities. Cellular bioenergetics were assessed through glycolysis and oxidative phosphorylation analyses. Western blotting was employed to examine epithelial-mesenchymal transition (EMT), glucose metabolism, and lipid metabolism markers. Cell cycle distribution was analyzed by flow cytometry. Additionally, a xenograft mouse model was developed for in vivo validation.
RESULTS: TP53 and RB1 mutations were associated with cisplatin concentration-dependent phenotypic transformation, with A549/DDP cells acquiring a more aggressive SCLC-like phenotype (In the article we call the A549/DDPSCLC cells). Analysis of cell bioenergetics profiling and Western blot analyses revealed enhanced glucose metabolism in A549/DDP1 μg/mL cells, while A549/DDPSCLC cells exhibited predominant lipid metabolism. Compound3K and Etomoxir specifically inhibit the activity of PKM2 and CPT1A, respectively, with Etomoxir demonstrating substantially inhibited A549/DDPSCLC cells growth and more cell cycle arrest in the G0/G1 phase. Combinatorial of Compound3K and Etomoxir effectively induced cell death in A549/DDPSCLC phenotype cells in vitro. Etomoxir alone or combined with Compound3K significantly inhibited tumor growth in vivo, with enhanced efficacy in the combination group.
CONCLUSIONS: This study provides the first evidence of cisplatin concentration-dependent metabolic reprogramming during NSCLC-to-SCLC transformation. We identified a phenotypic transition from NSCLC to SCLC accompanied by a metabolic shift from glucose to fatty acid metabolism, offering new insights into therapeutic strategies for treatmentresistant lung cancer.

Keywords: RB1 ; TP53 ; Fatty acid metabolism; Glucose metabolism; NSCLC; Phenotype

DOI: https://doi.org/10.1007/s00432-025-06164-3