A new analysis of non-small cell lung cancer reveals that dysregulated developmental programs are central to lung adenocarcinoma biology. The study identifies activation of branching morphogenesis as a marker of poorer prognosis and resistance to therapy.
Investigators examined two lung developmental programs-alveogenesis and branching morphogenesis-across multiple datasets. In lung adenocarcinoma, branching morphogenesis activation was heterogeneous and clinically significant. Across five cohorts totaling 1,646 patients, high activity of this program was linked to reduced 5-year overall survival, independent of stage and age.
TP53 pathway alteration appears to drive this cellular plasticity. TP53 mutations were found in 66% of branching morphogenesis high tumors, compared to 30% of low tumors. Mouse models confirmed that combined Kras activation and Trp53 deletion reduced alveogenesis and increased branching morphogenesis.
This plasticity also tracks with therapy resistance. In tyrosine kinase inhibitor-treated patients, branching morphogenesis activation was higher in recurrent disease. In EGFR-mutant cases, it was associated with poorer disease-free survival after third-generation EGFR inhibitor treatment. The signal extended to immunotherapy, where high branching morphogenesis tumors had reduced progression-free survival.
At the cellular level, branching morphogenesis activation reflected loss of alveolar type 2 lineage and acquisition of a basal-like phenotype. Type I interferon signaling promoted this phenotype in TP53-mutant cells.