Ya, V. | bioRxiv Science

bioRxiv2024

Airway injury induces alveolar epithelial and mesenchymal responses mediated by macrophages

Airway injury activates local progenitors and stimulates cell-cell interactions to restore homeostasis, but it is unknown how distal niches are impacted. We utilized mouse models of airway-specific epithelial injury to examine secondary tissue-wide alveolar and immune responses. Single-cell transcriptomics and in vivo validation of mouse models of airway-specific epithelial injury revealed transient, tissue-wide proliferation of alveolar type 2 (AT2) progenitor cells after club cell-specific injury or ablation. Myeloid cells exhibited altered gene expression after club cell loss and were detectable in the bronchoalveolar lavage fluid. The AT2 cell proliferative response was reliant on alveolar macrophages (AMs) exhibiting an injury-induced gene expression program. Overall, these results demonstrate that acute airway damage can trigger myeloid-mediated lung alveolar responses that may contribute to disease susceptibility or dysfunction.

cell biology↗

bioRxiv2024

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

Glycine 12 mutations in the GTPase KRAS (KRASG12) are a known initiating event for lung adenocarcinoma (LUAD) with broad clinical relevance. KRASG12 mutations 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 KRASG12D with temporal resolution. In AT2WT organoids, a transient injury/plasticity state preceded AT2 self-renewal and AT1 differentiation. Early-stage AT2KRAS cells exhibited perturbed gene expression dynamics most noted by retention of the injury/plasticity state. At later time points in tumorigenesis, AT2KRAS cells 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 AT2KRAS cells of LUAD in patients, mice, and organoids was distinguishable from AT2WT states by altered receptor expression, including co-expression of ITGA3 and SRC. The combination of clinically relevant KRASG12D and SRC inhibitors to target the oncogenic injury cell state impaired AT2KRAS organoid 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.

cancer biology↗