Transcriptome and methylome analysis reveals three cellular origins of pituitary tumors

Abstract

Pituitary adenomas (PA) are the second most common intracranial tumors. These neoplasms are classified according to the hormone they produce. The majority of PA occur sporadically, and their molecular pathogenesis is incompletely understood. The present transcriptomic and methylomic analysis of PA revealed that they segregate into three molecular clusters according to the transcription factor driving their terminal differentiation. First cluster, driven by NR5A1, consists of clinically non-functioning PA (CNFPA), comprising gonadotrophinomas and null cell; the second cluster consists of clinically evident ACTH adenomas and silent corticotroph adenomas, driven by TBX19; and the third, POU1F1-driven TSH-, PRL- and GH-adenomas, segregated together. Genes such as CACNA2D4, EPHA4 and SLIT1, were upregulated in each of these three clusters, respectively. Pathway enrichment analysis revealed specific alterations of these clusters: calcium signaling pathway in CNFPA; renin-angiotensin system for ACTH-adenomas and fatty acid metabolism for the TSH-, PRL-, GH-cluster. Non-tumoral pituitary scRNAseq data confirmed that this clustering also occurs in normal cytodifferentiation. Deconvolution analysis identify potential mononuclear cell infiltrate in PA consists of dendritic, NK and mast cells. Our results are consistent with a divergent origin of PA, which segregate into three clusters that depend on the specific transcription factors driving late pituitary cytodifferentiation.

Proteomic and Transcriptomic Analysis Identify Spliceosome as a Significant Component of the Molecular Machinery in the Pituitary Tumors Derived from POU1F1- and NR5A1-Cell Lineages

“…Our results underscored the participation of spliceosome components in the molecular machinery of the pituitary tumors pathogenesis derived from POU1F1and NR5A1-cell lineages and the alteration of the mRNA splicing patterns characteristic to each tumor. These tumor-specific spliceosome components and mRNA isoforms generated could support the notion that the pituitary tumors arise from divergent cell lineage origins or that they develop from partially committed pituitary stem cells, previously proposed by our group [10,11]. Similar results where the upregulation of several splicing factors in tumor-specific manner being observed in PA [12].…”

Pituitary Remodeling Throughout Life: Are Resident Stem Cells Involved?

“…However, these highly proliferative carcinomaresembling tumors do not immediately draw a parallel with the typically benign tumors that occur in the pituitary. Finally, a recent study, clustering pituitary tumors by RNA-seq analysis in three groups coinciding with canonical lineage transcription factors [i.e., TBX19, NR5A1 (SF1) and POU1F1 (PIT1)], did not reveal a transcriptomic link with the (normal) stem cell population, but suggested that the "tumor progenitor cells" (TSC) derive from already (partially) committed cells expressing the respective transcription factor (99).…”

Enhancing Gonadotrope Gene Expression Through Regulatory lncRNAs

“…Altered expression of lncRNAs is likely to underlie diverse cell phenotypes and behavior including oncogenesis, and several studies have examined their differential expression and possible functions in gonadotrope or nonfunctioning adenomas (NFPAs) which are primarily of gonadotrope origin ( 140 , 141 ). Analysis of the coexpression networks for lncRNAs and mRNAs in these tissues, compared with normal pituitary tissue, suggested that each lncRNA might have a large number of mRNA targets ( 142 , 143 ) and exposed lncRNAs that appear to play a role in tumor formation or invasiveness, while some of their targets are known to play roles in normal gonadotrope function.…”