Developmental programmes drive cellular plasticity, disease progression and therapy resistance in lung adenocarcinoma

Abstract

Cellular plasticity, involving loss of lineage determination and emergence of hybrid cell states, plays a pivotal role in non-small cell lung cancer (NSCLC) disease progression and therapy resistance. Here we use bulk and single-cell transcriptomic analysis of human NSCLC samples followed by multiplexed immunohistochemistry and experimental validation, to examine the role of developmental programmes, alveogenesis (ALV) and branching morphogenesis (BM) in regulating phenotypic diversity in NSCLC. This showed that NSCLC tumours suppressed the ALV programme and activated BM compared to control lung tissue, with consistent BM activation observed in squamous cell carcinomas (LUSC) and heterogeneous BM activation in adenocarcinomas (LUAD). In LUAD, BM was associated with TP53 mutations, morphological grade, poor overall survival rates and resistance to multiple targeted therapy modalities, whereas BM activation was not consistently prognostic in LUSC. Genetically engineered mouse models of KRAS-driven LUAD showed TP53 loss-of-function increased BM activation; and single cell analysis showed this process by tumour cell transdifferentiation from an alveolar to basal-like cell state. Pathway analysis and 3D organotypic cultures identified the involvement of type-I interferon signalling in driving BM activation in TP53-mutant LUAD. In summary, these findings identify novel prognostic biomarkers for therapy response in LUAD; and highlight a pro-tumorigenic role for type-I interferon signalling when TP53 pathway functionality is compromised.

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Identifiers

ORCID for Matthew Ellis: orcid.org/0000-0002-5264-0531

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

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