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Single cell RNAseq of human early stage lung adenocarcinoma with activating somatic KRAS mutations and associated normal lung tissues reveals alterations of key gene expression in alveolar type II pneumocytes

ABSTRACT: Mutant KRAS is the most common oncogenic driver of epithelial cancers. Nevertheless, the molecular changes induced by KRAS activation in primary epithelial cells remain unknown. Here, we determined transcriptional changes at single-cell resolution after KRAS activation in distal lung epithelial cell populations. We observed that activating somatic KRAS mutations had the most pronounced effect on alveolar type 2 (AT2) cells, one type of distal lung epithelial progenitor cells, whereas other distal lung epithelial cell types were similar to their wildtype KRAS counterparts. We found that tumor-associated AT2 cells highly expressed EPCAM and SFTPB, but had a significant reduction of STFPC and STFPD expression compared to their normal lung-associated counterparts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149655 | GEO | 2020/08/13

REPOSITORIES: GEO

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Project description:Alveoli are thin-walled sacs that serve as the gas exchange units of the lung. They are affected in devastating lung diseases including COPD, Idiopathic Pulmonary Fibrosis, and the major form (adenocarcinoma) of lung cancer, the leading cause of cancer deaths. The alveolar epithelium is composed of two morphologically distinct cell types: alveolar type (AT) 1 cells, exquisitely thin cells across which oxygen diffuses to reach the blood, and AT2 cells, specialized surfactant-secreting cells. Classical studies suggested that AT1 cells arise from AT2 cells during development and following injury, but more recent studies suggest other sources. Here we use histological and marker analysis, lineage tracing, and clonal analysis in mice to identify alveolar progenitor and stem cells and map their locations and potential in vivo. The results show that AT1 and AT2 cells arise independently during development from a bipotential progenitor. After birth, new AT1 cells derive from rare, long-lived, self-renewing AT2 cells, each producing a slowly expanding clonal focus of regenerated alveoli contiguous with the founder AT2 cell. This stem cell function of AT2 cells is broadly activated by diffuse AT1 cell injury, and AT2 self-renewal can be induced in vitro by EGF ligands and permanently activated in vivo by AT2 cell-specific targeting of the oncogenic KrasG12D allele, efficiently transforming AT2 cells into monoclonal adenomatous tumors that rapidly enlarge and prove fatal. Thus, there is a developmental switch in alveolar progenitor cells after birth, when mature AT2 cells function as facultative stem cells that contribute to local alveolar renewal, repair, and cancer. We propose that short-range signals from dying AT1 cells regulate AT2 stem cell activity: a signal transduced by EGFR-KRAS controls AT2 self-renewal and is hijacked during oncogenic transformation, and a separate signal controls reprogramming to AT1 cell fate. To compare expression between ATII and E18 BP populations, RNA was isolated from either population purified by FACS. Two populations are analyzed with 3 biological replicates per population.

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Single cell RNAseq of human early stage lung adenocarcinoma with activating somatic KRAS mutations and associated normal lung tissues reveals alterations of key gene expression in alveolar type II pneumocytes

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