Biology subjects

Chaikovsky, A.

Publications and source records attributed to Chaikovsky, A..

2 recordsLinked to original sources

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↗

bioRxiv2019

RB1 deletion in RB-pathway disrupted cells results in DNA damage and cancer progression.

Proliferative control in cancer cells is frequently disrupted by mutations in the RB-pathway. Intriguingly, RB1 mutations can arise late in tumorigenesis in cancer cells whose RB-pathway is already compromised by another mutation. In this study, we present evidence for increased DNA damage and instability in CDKN2A silenced cancer cells when RB1 mutations are induced. We generated isogenic RB1 mutant genotypes with CRISPR in a number of cell lines. Cells with even one mutant copy of RB1 have increased basal levels of DNA damage and increased mitotic errors. Elevated levels of reactive oxygen species as well as impaired homologous recombination repair underlie this DNA damage. When xenografted into immune compromised mice RB1 mutant cells exhibit an elevated propensity to seed new tumors in recipient lungs. This study offers evidence that late arising RB1 mutations can facilitate genome instability and cancer progression that are beyond the pre-existing proliferative control deficit.

cancer biology↗