Lung Basal Stem Cells Rapidly Repair DNA Damage Using the Error-Prone Nonhomologous End-Joining Pathway

Abstract

Lung squamous cell carcinoma (SqCC), the second most common subtype of lung cancer, is strongly associated with tobacco smoking and exhibits genomic instability. The cellular origins and molecular processes that contribute to SqCC formation are largely unexplored. Here we show that human basal stem cells (BSCs) isolated from heavy smokers proliferate extensively, whereas their alveolar progenitor cell counterparts have limited colony-forming capacity. We demonstrate that this difference arises in part because of the ability of BSCs to repair their DNA more efficiently than alveolar cells following ionizing radiation or chemical-induced DNA damage. Analysis of mice harbouring a mutation in the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key enzyme in DNA damage repair by nonhomologous end joining (NHEJ), indicated that BSCs preferentially repair their DNA by this error-prone process. Interestingly, polyploidy, a phenomenon associated with genetically unstable cells, was only observed in the human BSC subset. Expression signature analysis indicated that BSCs are the likely cells of origin of human SqCC and that high levels of NHEJ genes in SqCC are correlated with increasing genomic instability. Hence, our results favour a model in which heavy smoking promotes proliferation of BSCs, and their predilection for error-prone NHEJ could lead to the high mutagenic burden that culminates in SqCC. Targeting DNA repair processes may therefore have a role in the prevention and therapy of SqCC.

“Keaping” a lid on lung cancer: the Keap1-Nrf2 pathway

“…The transcriptome of lung basal cells most closely correlates with the transcriptional profile of human lung SqCC [46]. Indeed, landmark studies have revealed that different lung cancer subtypes arise from distinct lung epithelial cell lineages [47,48], suggesting that basal cells are the cells-of-origin of lung SqCC [49].…”

Cisplatin Increases Sensitivity to FGFR Inhibition in Patient-Derived Xenograft Models of Lung Squamous Cell Carcinoma

“…These models have been successfully established for solid tumors, including breast, melanoma, prostate, and pancreatic cancers and have been shown to recapitulate the phenotype, molecular profile, and therapeutic response of the patient's tumors (17)(18)(19). PDXs therefore constitute a highly clinically relevant system to study human solid tumors, even more specifically in lung cancer where whole genome sequencing analyses have revealed the complex heterogeneity and high frequency of genetic alterations in lung SqCC (20)(21)(22)(23).…”

BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous cell carcinoma

“…To further investigate the role of BCL11A in LUSC, we employed a recently described 3D organoid culture system for basal cells (BCs) from the trachea, as they have been suggested to be the cell of origin for LUSC 20 . BCs from human and mouse lungs have higher expression of BCL11A when compared to the other epithelial compartments (Supplementary Figure 4a and b) 21 . Therefore, we crossed the BCL11A ovx mice to R26-CreERT2 mice, which allowed us to induce Cre recombination by the administration of tamoxifen.…”

“… (a) RNA-Seq data analysed from Weeden et al 21 indicating that in human samples FACS fraction labelled as proximal BCs has approximately 400 fold increase in human BCL11A levels in comparison to other epithelial fractions. (b) RNA-Seq data from the same dataset indicating that mouse Bcl11a is approximately 500-1000 fold higher in basal fractions compared to other epithelial subtypes.…”