Single-Cell Analysis of Non-Functioning Gonadotroph Tumors Identifies Lineage Infidelity and Tumor Growth Programs
- 1Department of Neurosurgery, Harvard Medical School and Massachusetts General Hospital
Abstract
Non-functioning gonadotroph (NFG) tumors are the most common type of non-functioning pituitary adenomas and cause significant morbidity through mass effect. The molecular programs that distinguish NFG tumor cells from normal gonadotrophs and underlie tumor growth remain poorly understood. The aim of this study was to define transcriptional differences between NFG tumors and the normal anterior pituitary gland (APG) at single-cell resolution and to identify programs associated with tumor growth. We performed single-cell/nucleus RNA-sequencing of 21 NFG tumors and 8 APG samples, followed by integrative analyses of differential gene expression, regulatory networks, and cell-cell communication. We profiled 77,342 APG cells and 152,649 NFG tumor cells. Within the APG, we identified novel marker genes for each neuroendocrine cell type and distinct transcriptional signatures of anterior and posterior pituitary stem cell populations. Compared with normal gonadotrophs, tumor cells shared a core transcriptomic signature conserved across samples despite inter-tumor heterogeneity. Many conserved genes were markers of non-gonadotroph neuroendocrine and stem cells, suggesting that lineage infidelity is a recurrent feature of NFGs. Pseudobulk profiling identified genes positively correlated with tumor volume, including the known oncogenes CAD, BRF2, and SOX12. Finally, tumors showed increased proportions of myeloid, endothelial, and mural cells and crosstalk between tumor, immune, and stromal populations. This study defines transcriptomic signatures of cell identity in the normal APG and NFG tumors. Our findings reveal programs associated with NFG lineage infidelity and tumor growth, highlighting candidate predictors of patient outcomes and potential therapeutic targets.
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BibTeX
@misc{dennis2026singlecell,
title = {{Single-Cell Analysis of Non-Functioning Gonadotroph Tumors Identifies Lineage Infidelity and Tumor Growth Programs}},
author = {E. Dennis and G. D. Kim and Y. Zhou and C. A. Pereira and Q. Zhang and Y. R. Chang and G. v. d. Zee and I. v. Mullem and A. Tsytsykova and E. Conner and E. Tieu and R. Soberman and K. K. Miller and P. S. Jones and A. A. Petti},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.752250},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.752250v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Single-Cell Analysis of Non-Functioning Gonadotroph Tumors Identifies Lineage Infidelity and Tumor Growth Programs
AU - E. Dennis
AU - G. D. Kim
AU - Y. Zhou
AU - C. A. Pereira
AU - Q. Zhang
AU - Y. R. Chang
AU - G. v. d. Zee
AU - I. v. Mullem
AU - A. Tsytsykova
AU - E. Conner
AU - E. Tieu
AU - R. Soberman
AU - K. K. Miller
AU - P. S. Jones
AU - A. A. Petti
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.752250
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.752250v1
AB - Non-functioning gonadotroph (NFG) tumors are the most common type of non-functioning pituitary adenomas and cause significant morbidity through mass effect. The molecular programs that distinguish NFG tumor cells from normal gonadotrophs and underlie tumor growth remain poorly understood. The aim of this study was to define transcriptional differences between NFG tumors and the normal anterior pituitary gland (APG) at single-cell resolution and to identify programs associated with tumor growth. We performed single-cell/nucleus RNA-sequencing of 21 NFG tumors and 8 APG samples, followed by integrative analyses of differential gene expression, regulatory networks, and cell-cell communication. We profiled 77,342 APG cells and 152,649 NFG tumor cells. Within the APG, we identified novel marker genes for each neuroendocrine cell type and distinct transcriptional signatures of anterior and posterior pituitary stem cell populations. Compared with normal gonadotrophs, tumor cells shared a core transcriptomic signature conserved across samples despite inter-tumor heterogeneity. Many conserved genes were markers of non-gonadotroph neuroendocrine and stem cells, suggesting that lineage infidelity is a recurrent feature of NFGs. Pseudobulk profiling identified genes positively correlated with tumor volume, including the known oncogenes CAD, BRF2, and SOX12. Finally, tumors showed increased proportions of myeloid, endothelial, and mural cells and crosstalk between tumor, immune, and stromal populations. This study defines transcriptomic signatures of cell identity in the normal APG and NFG tumors. Our findings reveal programs associated with NFG lineage infidelity and tumor growth, highlighting candidate predictors of patient outcomes and potential therapeutic targets.
ER -