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Unraveling epithelial cell heterogeneity in adamantinomatous craniopharyngioma using single-cell and spatially resolved analysis

ABSTRACT: Adamantinomatous craniopharyngioma (ACP) is an intractable and histologically complex epithelial neoplasm with variable pathognomonic features, while its cellular composition, particularly the epithelial component, is poorly characterized. Herein, a single-nucleus transcriptome atlas specific to ACP was constructed by performing a single-nucleus RNA sequencing (snRNA-seq) survey of 55967 nuclei in 6 ACP samples from 3 patients. We revealed 6 epithelial subtypes with diverse molecular functions in ACP by integrating snRNA-seq, spatial transcriptomic (ST) and immunostaining data. Additionally, we investigated the potential regulatory mechanism of ACP calcification by performing a trajectory analysis and transcription factor regulon analysis. Finally, we characterized the molecular characteristics of neurons and discovered potential epithelial cell–neuron crosstalk in ACP tissues. Overall, this large-scale single-nucleus atlas combined with ST provides, for the first time, unprecedented insights into epithelial cell heterogeneity within ACP and can serve as a resource for further investigation of tumor dynamics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE215932 | GEO | 2024/06/26

REPOSITORIES: GEO

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Project description:Introduction: Pediatric adamantinomatous craniopharyngioma (ACP) is a histologically benign but clinically aggressive brain tumor that arises from the sellar/suprasellar region. Despite a high survival rate with current surgical and radiation therapy (75-95% at 10 years), ACP is associated with debilitating visual, endocrine, neurocognitive and psychological morbidity, resulting in exceptionally poor quality of life for survivors. Identification of an effective pharmacological therapy would drastically decrease morbidity and improve long term outcomes for children with ACP. Results: Using microarray analysis of 15 ACP patient samples, we have found several pharmaceutical targets that are significantly and consistently overexpressed in our panel of ACP relative to other pediatric brain tumors, pituitary tumors, normal pituitary and normal brain tissue. Among the most highly expressed are several targets of the kinase inhibitor dasatinib -- LCK, EPHA2 and SRC; EGFR pathway targets -- AREG, EGFR and ERBB3; and other potentially actionable cancer targets -- SHH, MMP9 and MMP12. We confirm by Western blot that a subset of these targets is highly expressed in ACP primary tumor samples. Discussion: We report here the first microarray gene expression analysis for ACP and the identification of targets for rational therapy. Experimental drugs targeting each of these gene products are currently being tested clinically and pre-clinically for the treatment of other tumor types. This study provides a rationale for further pre-clinical and clinical studies of novel pharmacological treatments for ACP. Development of pre-clinical mouse and cell culture models for ACP will further enable the translation of these targets from the lab to the clinic. Gene expression profiles were generated from surgical tumor and normal brain samples (n=210) using Affymetrix HG-U133 Plus 2.0 chips. Gene expression profiles of adamantinomatous craniopharyngioma (ACP) were compared to a cohort of other tumor samples and normal brain tissues, and analyzed via gene set enrichment (GSEA analysis) and hierarchical clustering analysis to identify high expression of potential drug targets. The sample metadata and processed data for the complete dataset, which includes reanalysis of 23 Samples from GSE26966, 33 Samples from GSE35493, and 42 Samples from GSE50385, are linked below as supplementary files.

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Unraveling epithelial cell heterogeneity in adamantinomatous craniopharyngioma using single-cell and spatially resolved analysis

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