In J02, L. Torres Fernández will investigate the molecular mechanisms driving hyperactivation of nonsense-mediated mRNA decay (NMD) in SCLC and determine whether NMD hyperactivation represents a conserved adaptive response to genomic instability and a therapeutically exploitable vulnerability across genomically unstable cancers. Genome-wide functional genetic screens and integrative computational analyses will identify the molecular regulators of NMD activity conserved across across genomically unstable cancers. Longitudinal spatial transcriptomics in genetically engineered mouse models of hypermutated SCLC will define the spatiotemporal dynamics of adaptive RNA surveillance during tumor evolution. Efficacy and safety of emerging NMD-targeted therapies will be evaluated in clinically relevant metastatic models of hypermutated SCLC using longitudinal molecular imaging. These studies will provide mechanistic insight into adaptive RNA surveillance in genomically unstable cancers and establish a framework for the clinical translation of NMD-targeted therapies.