Single-cell epigenetic landscape, microenvironment interactions, and gene regulatory modules of non-functioning pituitary adenomas.

The epigenetic landscape and tumor microenvironment (TME) interactions of non-functioning pituitary adenomas (NFPAs), benign tumors with high morbidity and recurrence rates, are not well characterized. We completed single-nucleus (sn) multiomics assays on 4 gonadotrope NFPAs (34,819 cells) and 11 non-diseased postmortem control pituitaries (51,535 cells), finding decreased proportions of tumor-associated endothelial cells and pericytes and increased proportions of macrophages. We identified bidirectional tumor-macrophage crosstalk comprising nine ligand-receptor interactions and experimentally validated the macrophage-initiated SFRP1-FZD6 interaction, whose predicted target genes CCND1, CDK6, SGK1, and TGFBR2 were linked to tumorigenesis. We uncovered coordinated gene expression and chromatin accessibility programs, which distinguished adenoma cells from gonadotropes. Integrated transcriptome-chromatin modeling revealed gene regulatory circuits (GRCs) that showed altered activity in adenoma cells and were regulated by transcription factors (TFs), including PBX3 and MEF2C. Our study provides insight into the altered epigenetic gene control landscape and TME processes of the NFPA tumor phenotype. Our data are freely available at https://rstudio-connect.hpc.mssm.edu/nfpa_browser/.