Single-Cell Analysis of Non-Functioning Gonadotroph Tumors Identifies Lineage Infidelity and Tumor Growth Programs
Non-functioning gonadotroph (NFG) tumors are the most common type of non-functioning pituitary adenomas and can cause significant symptoms due to mass effect. However, the molecular programs underlying NFG tumor growth and their relationship to the normal anterior pituitary gland (APG) are poorly understood. To gain a deeper understanding of NFG tumor biology in the context of the normal APG, we…
Gonadotroph (NFG) tumors represent the predominant form of non-functioning pituitary adenomas, causing noticeable issues due to their mass. Despite their prevalence, the biological mechanisms driving NFG tumor growth and their connection to the normal anterior pituitary gland (APG) remain unclear. To elucidate NFG tumor biology within the framework of the typical APG, researchers conducted single-cell/nucleus RNA-sequencing on 21 NFG tumors and 8 APG samples in humans, creating the most extensive genetic dataset of its kind yet.
This method yielded 77,342 cells from APG samples and 152,649 cells from NFG tumors. Analyzing the data revealed 77,342 unique cells from the APG and 152,649 from the NFG tumors. By comparing gene expression levels, they identified specific genes that distinguish each type of neuroendocrine cell within the APG and established unique transcriptional profiles for the anterior and posterior pituitary stem cell populations.
When they compared tumor transcriptomes to those of APG cells, they found that NFG tumor cells most closely resembled gonadotrophs, yet also showed a high presence of markers for thyrotrophs and somatotrophs. Importantly, there was no significant overlap with stem cell markers, indicating that NFG tumors most likely arise from differentiated gonadotroph cells but can adopt the transcriptional traits of other neuroendocrine cell types.
Pseudobulk analysis of NFG tumor cells also showed a strong positive correlation between tumor volume and 83 genes, including known oncogenes CAD, BRF2, and SOX12, as well as 16 zinc finger transcription factors. Finally, the study of the tumor microenvironment demonstrated increased numbers of myeloid, endothelial, and mural cell populations in tumor samples compared to APG samples, and revealed interactions between tumor and endothelial, mesenchymal, and immune populations through the VEGF, PDGF, and MIF signaling pathways.
This research uncovers new genetic profiles that determine the identity of both APG neuroendocrine cells and NFG tumor cells. The findings shed light on the molecular processes behind NFG lineage infidelity and tumor growth, offering promising insights into potential markers for patient prognosis and targets for therapeutic treatments.
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