In a recent study, researchers examined 246,102 single epithelial cells from 16 early-stage lung adenocarcinomas (LUADs) and 47 normal lung samples to understand the cellular processes involved in LUAD development. The analysis revealed diverse normal and cancer cell states within the epithelial cells, with cancer cell diversity strongly linked to LUAD-specific oncogenic drivers.

Specifically, KRAS mutant cancer cells displayed distinct transcriptional features, reduced differentiation, and low levels of aneuploidy. Non-malignant areas surrounding LUAD samples were found to be enriched with alveolar intermediate cells expressing elevated levels of KRT8, termed KRT8+ alveolar intermediate cells (KACs). These KACs exhibited reduced differentiation, increased plasticity, and driver KRAS mutations, with expression profiles associated with poor survival outcomes.

In experiments with mice exposed to tobacco carcinogens, researchers observed that KACs emerged before lung tumors and persisted even after carcinogen exposure ceased. The KACs acquired Kras mutations and demonstrated sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Lineage-labeling experiments indicated that KACs could serve as intermediates in the transformation of AT2 cells into tumor cells.

This study provides novel insights into the cellular states underlying LUAD development, suggesting potential targets for prevention and intervention strategies. The findings shed light on the early stages of LUAD progression and highlight the importance of understanding cellular processes in devising effective intervention approaches for lung cancer.