Lung adenocarcinoma (LUAD) progression is accompanied by changes in epithelial cell state, but how adult and developmental lung epithelial programs are retained, lost, or remodeled across disease stages remains incompletely defined. Here, we analyzed a harmonized single-cell RNA-sequencing cohort of twelve LUAD datasets and used adult and fetal lung atlases as complementary references to quantify epithelial program activity in cancer cells.
LUAD progression was associated with selective loss of distal alveolar and transitional epithelial programs. Positivity for the AT2/late-tip module decreased from 17.1% of cancer cells in early tumors to 5.4% in stage IV metastatic tumors, and the pre-terminal bronchiolar/AT0 module decreased from 12.1% to 2.7%. In contrast, the club/proximal-secretory module increased in advanced disease, but gene-level analyses indicated a shift away from canonical club markers toward stress-associated and alternative secretory genes. Smoking history modified the early-stage baseline of the AT2/late-tip program, although all smoking groups converged toward low prevalence in advanced disease.
Direct scoring against fetal-reference epithelial signatures showed that LUAD progression was not characterized by broad fetal-like reactivation. Most fetal-reference signatures, including fetal AT1, AT2, club, late-tip, and late-stalk programs, were depleted in advanced tumors. By contrast, early-tip and, to a lesser extent, early-stalk signatures showed selective enrichment, with early-tip positivity increasing despite reduced per-cell score intensity.
Together, these results indicate that epithelial remodeling during LUAD progression is not a simple process of global dedifferentiation. Instead, LUAD progression involves selective loss of alveolar and transitional distal epithelial programs, divergence of secretory trajectories toward stress-associated states, and restricted reactivation of early developmental-reference programs. This atlas-guided framework provides interpretable benchmarks for quantifying cancer cell plasticity during LUAD progression.
