Use of integrated spatial transcriptomics and histopathological analysis in adamantinomatous craniopharyngiomas to identify stromal cells as a new cellular source of leukemia inhibitory factor

OBJECTIVE Adamantinomatous craniopharyngioma (ACP) is an epithelial tumor that occurs in the sellar region of the human brain. Despite resection, relapse is frequent with poor prognosis. To facilitate the development of new therapy for ACP, the authors examined the spatial distribution, cell of origin, and potential biological functions of leukemia inhibitory factor (LIF), an important stem cell self-renewal regulator, in a series of ACP tumors. METHODS The transcriptional sites of LIF and LIF receptor (LIFR) were determined by single-cell sequencing and space transcriptome analysis. LIF and LIFR distribution characteristics in different histopathological regions were detected with immunohistochemistry and immunofluorescence analysis. The relationships between the regional distributions of different tissues and tumor imaging characteristics, tumor cell stemness, cell proliferation, LIF expression, and patient prognosis were analyzed. RESULTS The authors’ analysis of 39 ACPs detected LIF overexpression that was selectively enriched in cell clusters. In addition to the discovery of the stromal cells in the interstitial region, palisade epithelium, and stellate reticulum as the source cells of LIF production, the authors also revealed that LIFR was primarily generated by the cell clusters. Examination of differentially expressed genes between LIF-high and LIF-low ACP tumors indicated that the binding of LIF to LIFR may lead to the activation of the PI3K-AKT signaling pathway. Further analysis showed enrichment of LIF expression in β-catenin–positive cell clusters expressing stem cell markers of CD44, supporting its role in stem cell self-renewal. Integrated analysis with diagnostic imaging found higher level expression of LIF in cystic tumors than in solid tumors, displaying a trend toward poorer prognosis. CONCLUSIONS This study confirmed for the first time that LIF in ACP mainly originates from tumor microenvironment stroma. The authors’ data suggest that future efforts should also include tumor stromal cells as a novel cellular and/or molecular target when developing new anticancer therapies against ACP.