Single‐cell transcriptomics provides insights into the origin and microenvironment of human oesophageal high‐grade intraepithelial neoplasia

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Abstract Background High‐grade intraepithelial neoplasia (HIN) is the precursor of oesophageal squamous cell carcinoma. The molecular and functional properties of HIN are determined by intrinsic origin cells and the extrinsic microenvironment. Yet, these factors are poorly understood. Methods We performed single‐cell RNA sequencing of cells from HINs and adjacent tissues from the human oesophagus. We analysed the heterogeneity of basal layer cells and confirmed it using immunostaining. Aneuploid cells in HIN were studied using primary cell culture combined with karyotype analysis. We reconstructed the lineage relationship between tumour and normal populations based on transcriptome similarity. Integration analysis was applied to our epithelial data and published invasive cancer data, and results were confirmed by immunostaining and 3D organoid functional experiments. We also analysed the tumour microenvironment of HIN. Results The basal layer contained two cell populations: KRT15highSTMN1low and KRT15highSTMN1high cells, which were located mainly in the interpapillary and papillary zones, respectively. The KRT15highSTMN1low population more closely resembled stem cells and transcriptome similarity revealed that HIN probably originated from these slow‐cycling KRT15highSTMN1low cells. 3D Organoid experiments and RNA‐sequencing showed that basal‐cell features and the differentiation ability of the normal epithelium were largely retained in HIN, but may change dramatically in tumour invasion stage. Moreover, the tumour microenvironment of HIN was characterised by both inflammation and immunosuppression. Conclusions Our study provides a comprehensive single‐cell transcriptome landscape of human oesophageal HIN. Our findings on the origin cells and unique microenvironment of HIN will allow for the development of strategies to block tumour progression and even prevent cancer initiation.

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