Lrig1 expression identifies airway basal cells with high proliferative capacity and restricts lung squamous cell carcinoma growth

Abstract

Lung squamous cell carcinoma (LUSC) accounts for a significant proportion of cancer deaths worldwide, and is preceded by the appearance of progressively disorganised pre-invasive lesions in the airway epithelium. Yet the biological mechanisms underlying progression of pre-invasive lesions into invasive LUSC are not fully understood. LRIG1 is downregulated in pre-invasive airway lesions and invasive LUSC tumours and this correlates with decreased lung cancer patient survival.Using an Lrig1 knock-in reporter mouse and human airway epithelial cells collected at bronchoscopy, we show that during homeostasis LRIG1 is heterogeneously expressed in the airway epithelium. In basal airway epithelial cells, the suspected cell of origin of LUSC, LRIG1 identifies a subpopulation of progenitor cells with higher in vitro proliferative and self-renewal potential in both the mouse and human. Using the N-nitroso-tris-chloroethylurea (NTCU)-induced murine model of LUSC, we find that Lrig1 loss-of-function leads to abnormally high cell proliferation during the earliest stages of pre-invasive disease and to the formation of significantly larger invasive tumours, suggesting accelerated disease progression.Together, our findings identify LRIG1 as a marker of basal airway progenitor cells with high proliferative potential and as a regulator of pre-invasive lung cancer progression. This work highlights the clinical relevance of LRIG1 and the potential of the NTCU-induced LUSC model for functional assessment of candidate tumour suppressors and oncogenes.

Simultaneous isolation of proximal and distal lung progenitor cells from individual mice using a 3D printed guide reduces proximal cell contamination of distal lung epithelial cell isolations

“…We found 3,270 differentially expressed genes between distal progenitors isolated with the 3DLD or classic method ( Figure 3 G). Interestingly, genes associated with the proximal epithelium, such as Krt14 , were among the most differentially expressed as well as genes recently associated with highly proliferative basal cells ( Pbk ) ( Succony et al., 2021 ). Despite differences in organoid size distribution ( Figure 3 E), organoids formed from both isolation methods resulted in transcriptional profiles which were distinct from their initial starting populations and highly similar to one another ( Figure 3 F).…”

Simultaneous isolation of proximal and distal lung progenitor cells from individual mice using a 3D printed guide reduces proximal cell contamination of distal lung epithelial cell isolations

“…We found 3270 differentially expressed genes between distal progenitors isolated with the 3DLD or classic method (Figure 3G). Interestingly, among the most differentially expressed genes are those known to be associated with the proximal epithelium, such as Krt14 , as well as genes recently associated with highly proliferative basal cells ( Pbk )(Succony et al, 2021). However, organoids formed from both isolation methods seemed to result in transcriptional profiles which were distinct and more similar to one another than the differences we observed in the initial cell populations from each isolation (Figure 3F).…”