Epithelial plasticity shapes intratumoral heterogeneity and cell lineages in early- stage lung cancer

Abstract

Intratumoral heterogeneity (ITH) has been investigated primarily in locally advanced or metastatic cancer; how-ever, much less is known about ITH in early- stage cancer, and the origins of ITH are poorly understood. Through single- cell and spatial transcriptomics of early- stage ground- glass opacity (GGO)–like lung adenocarcinoma (LUAD) (14 patients; 103,375 cells), we systematically define tumor states and demonstrate that pervasive transcriptional ITH exists in early- stage LUAD. Lineage diversification through epithelial plasticity, via a shift to less differentiated states and transdifferentiation, underlies a critical dimension of early ITH in lung cancer. We further reveal that de-creased differentiation serves as a pathognomonic feature of malignant transformation and predicts poor prog-nosis. Notably, we identified a unique transitional state during AT2- to- AT1 transdifferentiation with activated tumor- suppressive pathways/genes. Integrative analysis of scRNA- seq, CUT&Tag, and bulk RNA- seq reveals that KLF4 and JDP2 are key transcription factors that reprogram LUAD into transitional state and inhibit progression. These findings elucidate ITH mechanisms in early- stage cancer and propose epithelial plasticity- targeted therapies.