Developmental programmes drive cellular plasticity, disease progression and therapy resistance in lung adenocarcinoma.

Cellular plasticity is central to non-small cell lung cancer (NSCLC) disease progression and linked to aberrant regulation of developmental programmes. Here, we investigated the contribution of two developmental programmes, alveogenesis (ALV) and branching morphogenesis (BM), to NSCLC disease progression. ALV and BM inversely correlated across multiple transcriptome datasets. In squamous carcinomas (LUSC), ALV suppression and BM activation were consistently observed relative to controls, but these features were not prognostic. In contrast, adenocarcinomas (LUAD) displayed heterogeneous BM activation, associated with poor overall survival in several observational cohorts (n = 5) and resistance to tyrosine kinase inhibitors or immune checkpoint blockade. Exome sequencing linked TP53 pathway mutations to BM activation in LUAD, which was validated in conditional Trp53 knock-out mouse models. Single-cell RNA-sequencing combined with multiplexed immunohistochemistry showed LUAD BM activation reflected increased morphological grade with tumour cells transdifferentiating to a basal-like cell state. Finally, 3D organotypic cultures identified type-I interferon signalling as a driver of BM activation in TP53-mutant LUAD. Collectively, our findings reveal a novel TP53-interferon axis that promotes transcriptomic plasticity in LUAD, with important implications for biomarker and therapeutic target discovery.