Based on the observation made within A05 during the first funding period, that neuroendocrine and non-neuroendocrine SCLC subtypes have distinct dependencies on glutathione, C. Frezza and his colleagues performed preliminary analyses and found drastic changes in sulfur metabolism, and proline and creatine synthesis between both subtypes. Moving forward, the team will now employ metabolomics coupled with transcriptomics/genomics and computational biology to seek to identify comprehensively the metabolism-related heterogeneity that is present in SCLC and to determine, to what extent this heterogeneity is reflective of the different transcriptional subtypes or may even define new subtype classes based upon metabolic state. Working closely with A05, they will furthermore strive to determine, how such metabolic heterogeneity impacts glutathione metabolism in neuroendocrine and non-neuroendocrine versions of SCLC and thereby impact ferroptosis sensitivity.