Early-stage lung cancer is driven by a transitional cell state dependent on a KRAS-ITGA3-SRC axis.

Glycine-12 mutations in the GTPase KRAS (KRAS G12 ) are an initiating event for development of lung adenocarcinoma (LUAD). KRAS G12 mutations promote cell-intrinsic rewiring of alveolar type-II progenitor (AT2) cells, but to what extent such changes interplay with lung homeostasis and cell fate pathways is unclear. Here, we generated single-cell RNA-seq (scRNA-seq) profiles from AT2-mesenchyme organoid co-cultures, mice, and stage-IA LUAD patients, identifying conserved regulators of AT2 transcriptional dynamics and defining the impact of KRAS G12D mutation with temporal resolution. In AT2 WT organoids, we found a transient injury/plasticity state preceding AT2 self-renewal and AT1 differentiation. Early-stage AT2 KRAS cells exhibited perturbed gene expression dynamics, most notably retention of the injury/plasticity state. The injury state in AT2 KRAS cells of patients, mice, and organoids was distinguishable from AT2 WT states via altered receptor expression, including co-expression of ITGA3 and SRC. The combination of clinically relevant KRAS G12D and SRC inhibitors impaired AT2 KRAS organoid growth. Together, our data show that an injury/plasticity state essential for lung repair is co-opted during AT2 self-renewal and LUAD initiation, suggesting that early-stage LUAD may be susceptible to interventions that target specifically the oncogenic nature of this cell state.