Early-stage lung adenocarcinoma is driven by an injury-associated, plastic cell state dependent on a KRAS-ITGA3-SRC axis

Abstract

AbstractGlycine 12 mutations in the GTPase KRAS (KRASG12) are a known initiating event for lung adenocarcinoma (LUAD) with broad clinical relevance. KRASG12mutations promote cell-intrinsic rewiring of the lung alveolar type II progenitor (AT2) cells, but to what extent such changes interplay with pathways essential for lung homeostasis and cell fate is unclear. We used single-cell RNA-seq (scRNA-seq) from AT2-mesenchyme organoid co-cultures, mouse models, and stage IA LUAD patient samples to identify conserved regulators of AT2 cell transcriptional dynamics and the impact of KRASG12Dwith temporal resolution. In AT2WTorganoids, a transient injury/plasticity state preceded AT2 self-renewal and AT1 differentiation. Early-stage AT2KRAScells exhibited perturbed gene expression dynamics most noted by retention of the injury/plasticity state. At later time points in tumorigenesis, AT2KRAScells consisted of heterogeneous populations that could be defined by either the injury state or high expression of an AT2 cell signature. The injury state in AT2KRAScells of LUAD in patients, mice, and organoids was distinguishable from AT2WTstates by altered receptor expression, including co-expression of ITGA3 and SRC. The combination of clinically relevant KRASG12Dand SRC inhibitors to target the oncogenic injury cell state impaired AT2KRASorganoid growth. Thus, an injury/plasticity signature characterized as an essential step in lung repair is used during alveolar cell self-renewal and during initiation and progression of LUAD. Early-stage lung cancer may be susceptible to intervention by targeting the oncogenic-specific nature of this cell state.