Investigating the role of developmental programmes in lung adenocarcinoma progression

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide and despite much progress the survival rate remains poor. This highlights the need for a better understanding of the disease and for improved therapies. Healthy lungs show little cell turnover under homeostatic conditions, yet lung epithelial cells can display remarkable plasticity. This plasticity is most evident during lung development, when early progenitor cells proliferate and give rise to all epithelial lineages in the lung, but also during lung regeneration (as a response to injury) and in cancer. In this project it was hypothesised that developmental transcriptional programmes active during lung development (alveogenesis – ALV, branching morphogenesis – BM) are hijacked in non-small cell lung cancer (NSCLC). To investigate this the expression of gene signatures of ALV/BM was analysed in large NSCLC cohorts containing whole-tumour transcriptomics data. Reactivation of developmental BM was found to drive disease progression and to correlate with poor survival in lung adenocarcinomas (LUAD) but not in lung squamous cell carcinomas (LUSC). Next, to understand the transcriptomic changes at the single cell level as well as to identify potential cell types that could regulate BM expression in cancer, cell-type specific gene co-expression modules were identified in epithelial and non-epithelial cells. This revealed that BM reactivation was associated with de-differentiation of LUAD cells that led to a loss of their alveolar lineage commitment and acquisition of basal-like features. Furthermore, an intercellular correlation network of the tumour microenvironment implicated fibroblasts (and to a lesser extent macrophages) as potential regulators of BM reactivation. This was later confirmed in vitro in a 3D tri-culture system and shown to be mediated by type I interferon signalling. BM expression in LUAD was also associated with the mutational status of KRAS and TP53 genes, where tumours with TP53 mutations (but not KRAS) were found to have the highest BM scores. Finally, type I interferon signalling was identified as a potential driver of high BM expression in LUAD tumours carrying TP53 mutations.

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ORCID for Chris Hanley: orcid.org/0000-0003-3816-7220

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