Prymidis, D. | bioRxiv Science

bioRxiv2026

Cell state-specific metabolic networks govern ferroptosis versus apoptosis in small cell lung cancer

Cellular heterogeneity and plasticity are hallmarks of cancer that contribute to tumor growth and therapy resistance. Here we investigated metabolic heterogeneity in small cell lung cancer (SCLC), an aggressive neuroendocrine (NE) cancer type. Through integrated transcriptomic and metabolomic analyses, we identified a universal dependency on exogenous cysteine/cystine (Cys) across all NE/non-NE SCLC cell states. Notably, NE and non-NE cells with low levels of the ASCL1 transcription factor die from ferroptosis upon Cys depletion. In contrast, ASCL1-high cells die from apoptosis but are ferroptosis resistant. This resistance to ferroptosis is driven by the direct upregulation of the gene coding for the GCH1 enzyme by ASCL1, which results in higher levels of the BH4/BH2 antioxidants. Accordingly, combining cysteine depletion with BH4/BH2 synthesis inhibition effectively reduces tumor growth in patient-derived xenografts. This work elucidates distinct metabolic states in SCLC and suggests new approaches to induce cell death in this lethal form of cancer.

cancer biology↗

bioRxiv2025

Integrated metabolomics data analysis to generate mechanistic hypotheses with MetaProViz

With the growing number of metabolomics and lipidomics studies, robust strategies for bioinformatic analyses are increasingly important. However, the absence of standardized and reproducible workflows, coupled with ambiguous metabolite annotations, hampers effective analysis, particularly when integrating prior knowledge with metabolomics data. Moreover, the limited availability of comprehensive, curated prior knowledge further limits functional analyses and reduces the extraction of meaningful biological insights. Here we present MetaProViz (Metabolomics Processing, functional analysis and Visualization), a free open-source R package for metabolomics data analysis that integrates prior knowledge to generate mechanistic hypotheses (https://saezlab.github.io/MetaProViz/). MetaProViz offers a flexible framework consisting of five modules: processing, differential analysis, prior knowledge integration, functional analysis and visualisation, applicable to both intracellular and exometabolomics experiments. To improve functional analysis, we created the Metabolism Signature Database (MetSigDB), a collection of annotated metabolite sets. MetSigDB includes classical pathway-metabolite sets, metabolite-receptor and metabolite-transporter sets, and chemical class-metabolite sets. In addition, MetaProViz enables the conversion of gene sets to metabolite sets by using enzyme-metabolic reaction associations. In addition, MetaProViz translates between metabolite identifiers of commonly used databases, analyzes mapping ambiguities and completes missing annotations. The MetaProViz functional analysis toolkit includes sample metadata analysis, classical enrichment analysis and biologically informed clustering. We showcase MetaProViz functionalities using kidney cancer metabolomics data from cell lines, cell-culture media, and tumour tissue. We found increased methionine usage in clear-cell renal cell carcinoma (ccRCC) cell lines in line with decreased methionine levels in tumour samples. Further, we link this observation to enzymes and transporters crucial for overall survival in ccRCC and suggest that the increased methionine usage reflects the elevated DNA-hypermethylation landscape, a known characteristic in ccRCC. In summary, MetaProViz facilitates and improves the analysis and interpretation of metabolomics data. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/670781v1_ufig1.gif" ALT="Figure 1"> View larger version (79K): org.highwire.dtl.DTLVardef@10a7a39org.highwire.dtl.DTLVardef@de4c4forg.highwire.dtl.DTLVardef@64041dorg.highwire.dtl.DTLVardef@4a427c_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗