Rouhani, Maral; (2025) Characterising the functional, transcriptomic and genomic landscape of the upper airway epithelium. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Head and Neck cancer, which includes sinonasal and laryngeal cancers, is the 8th most common cancer in the UK. Treatment typically involves chemoradiotherapy and surgical resection which can leave patients with devastating cosmetic and functional outcomes. Tobacco smoke is a common risk factor in this group of cancers, yet despite this shared environmental exposure, sinonasal and laryngeal cancers in the upper airway occur at much lower rates than lung cancers in the lower airway, suggesting distinct protective mechanisms. This thesis explores airway epithelial biology across anatomical subsites to understand differential cancer susceptibility between upper and lower airways, also challenging the "one airway" hypothesis. Functional analysis reveals that while nasal and tracheal basal cells appeared similar in bulk culture, tracheal samples consistently showed higher populations of PDPN-high basal cells with superior clonal capacity. Single-cell RNA sequencing demonstrates extensive transcriptional heterogeneity between compartments. In the nasal epithelium, there was enrichment for secretory cells and protective pathways including oxidative stress responses and SLC7A11-mediated ferroptosis protection, whilst the tracheal tissue demonstrated higher basal cell proportions and inflammatory pathway activation. Mutational landscape analysis describes herein the first comprehensive view of somatic mutations across normal upper airway subsites, revealing unexpected patterns where mutational burden peaks at the respiratory supraglottis before declining toward the trachea, along with enrichment of the SBS4 tobacco-associated signature. Mutation rates increase with age in laryngeal and tracheal subsites but not in the nose, despite comparable carcinogen exposure. Experimental validation using NTCU-induced carcinogenesis in mice, finding lower grade lesions in the nose compared to more several distal lung lesions, further suggests intrinsic protective mechanisms. These findings suggest fundamental differences in stem cell biology and protective mechanisms across airway subsites, which can be mined further to inform novel cancer prevention strategies and therapeutic targets.

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