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Cancer Cell Jan 2020Pituitary neuroendocrine tumors (PitNETs) are common, with five main histological subtypes: lactotroph, somatotroph, and thyrotroph (POU1F1/PIT1 lineage); corticotroph...
Pituitary neuroendocrine tumors (PitNETs) are common, with five main histological subtypes: lactotroph, somatotroph, and thyrotroph (POU1F1/PIT1 lineage); corticotroph (TBX19/TPIT lineage); and gonadotroph (NR5A1/SF1 lineage). We report a comprehensive pangenomic classification of PitNETs. PitNETs from POU1F1/PIT1 lineage showed an epigenetic signature of diffuse DNA hypomethylation, with transposable elements expression and chromosomal instability (except for GNAS-mutated somatotrophs). In TPIT lineage, corticotrophs were divided into three classes: the USP8-mutated with overt secretion, the USP8-wild-type with increased invasiveness and increased epithelial-mesenchymal transition, and the large silent tumors with gonadotroph transdifferentiation. Unexpected expression of gonadotroph markers was also found in GNAS-wild-type somatotrophs (SF1 expression), challenging the current definition of SF1/gonadotroph lineage. This classification improves our understanding and affects the clinical stratification of patients with PitNETs.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cell Lineage; Chromosome Aberrations; DNA Methylation; Endopeptidases; Endosomal Sorting Complexes Required for Transport; Epigenesis, Genetic; Epigenome; Exome; Female; Humans; Male; Middle Aged; Mutation; Neoplasm Invasiveness; Neuroendocrine Tumors; Pituitary Gland; Pituitary Neoplasms; Prognosis; Transcriptome; Ubiquitin Thiolesterase; Young Adult
PubMed: 31883967
DOI: 10.1016/j.ccell.2019.11.002 -
Neuro-oncology Nov 2021Pituitary neuroendocrine tumors (PitNETs) are the second most common intracranial tumor. We lacked a comprehensive understanding of the pathogenesis and heterogeneity of...
BACKGROUND
Pituitary neuroendocrine tumors (PitNETs) are the second most common intracranial tumor. We lacked a comprehensive understanding of the pathogenesis and heterogeneity of these tumors.
METHODS
We performed high-precision single-cell RNA sequencing for 2679 individual cells obtained from 23 surgically resected samples of the major subtypes of PitNETs from 21 patients. We also performed single-cell multi-omics sequencing for 238 cells from 5 patients.
RESULTS
Unsupervised clustering analysis distinguished all tumor subtypes, which was in accordance with the classification based on immunohistochemistry and provided additional information. We identified 3 normal endocrine cell types: somatotrophs, lactotrophs, and gonadotrophs. Comparisons of tumor and matched normal cells showed that differentially expressed genes of gonadotroph tumors were predominantly downregulated, while those of somatotroph and lactotroph tumors were mainly upregulated. We identified novel tumor-related genes, such as AMIGO2, ZFP36, BTG1, and DLG5. Tumors expressing multiple hormone genes showed little transcriptomic heterogeneity. Furthermore, single-cell multi-omics analysis demonstrated that the tumor had a relatively uniform pattern of genome with slight heterogeneity in copy number variations.
CONCLUSIONS
Our single-cell transcriptome and single-cell multi-omics analyses provide novel insights into the characteristics and heterogeneity of these complex neoplasms for the identification of biomarkers and therapeutic targets.
Topics: DNA Copy Number Variations; Humans; Neuroendocrine Tumors; Pituitary Gland; Pituitary Neoplasms; Transcriptome
PubMed: 33908609
DOI: 10.1093/neuonc/noab102 -
Nature Communications Oct 2020The anterior pituitary gland plays a central role in regulating various physiological processes, including body growth, reproduction, metabolism and stress response....
The anterior pituitary gland plays a central role in regulating various physiological processes, including body growth, reproduction, metabolism and stress response. Here, we perform single-cell RNA-sequencing (scRNA-seq) of 4113 individual cells from human fetal pituitaries. We characterize divergent developmental trajectories with distinct transitional intermediate states in five hormone-producing cell lineages. Corticotropes exhibit an early intermediate state prior to full differentiation. Three cell types of the PIT-1 lineage (somatotropes, lactotropes and thyrotropes) segregate from a common progenitor coexpressing lineage-specific transcription factors of different sublineages. Gonadotropes experience two multistep developmental trajectories. Furthermore, we identify a fetal gonadotrope cell subtype expressing the primate-specific hormone chorionic gonadotropin. We also characterize the cellular heterogeneity of pituitary stem cells and identify a hybrid epithelial/mesenchymal state and an early-to-late state transition. Here, our results provide insights into the transcriptional landscape of human pituitary development, defining distinct cell substates and subtypes and illustrating transcription factor dynamics during cell fate commitment.
Topics: Cell Differentiation; Cells, Cultured; Female; Fetus; Gene Expression Regulation, Developmental; Gonadotrophs; Gonadotropins; Humans; Male; Pituitary Gland, Anterior; Proteins; Sequence Analysis, RNA; Single-Cell Analysis; Transcription Factors; Transcriptome
PubMed: 33077725
DOI: 10.1038/s41467-020-19012-4 -
Frontiers in Endocrinology 2017Gonadotrophs are basophilic cells of the anterior pituitary gland specialized to secrete gonadotropins in response to elevation in intracellular calcium concentration.... (Review)
Review
Gonadotrophs are basophilic cells of the anterior pituitary gland specialized to secrete gonadotropins in response to elevation in intracellular calcium concentration. These cells fire action potentials (APs) spontaneously, coupled with voltage-gated calcium influx of insufficient amplitude to trigger gonadotropin release. The spontaneous excitability of gonadotrophs reflects the expression of voltage-gated sodium, calcium, potassium, non-selective cation-conducting, and chloride channels at their plasma membrane (PM). These cells also express the hyperpolarization-activated and cyclic nucleotide-gated cation channels at the PM, as well as GABA, nicotinic, and purinergic P2X channels gated by γ-aminobutyric acid (GABA), acetylcholine (ACh), and ATP, respectively. Activation of these channels leads to initiation or amplification of the pacemaking activity, facilitation of calcium influx, and activation of the exocytic pathway. Gonadotrophs also express calcium-conducting channels at the endoplasmic reticulum membranes gated by inositol trisphosphate and intracellular calcium. These channels are activated potently by hypothalamic gonadotropin-releasing hormone (GnRH) and less potently by several paracrine calcium-mobilizing agonists, including pituitary adenylate cyclase-activating peptides, endothelins, ACh, vasopressin, and oxytocin. Activation of these channels causes oscillatory calcium release and a rapid gonadotropin release, accompanied with a shift from tonic firing of single APs to periodic bursting type of electrical activity, which accounts for a sustained calcium signaling and gonadotropin secretion. This review summarizes our current understanding of ion channels as signaling molecules in gonadotrophs, the role of GnRH and paracrine agonists in their gating, and the cross talk among channels.
PubMed: 28649232
DOI: 10.3389/fendo.2017.00126 -
Frontiers in Endocrinology 2020The pituitary is a master endocrine gland that developed early in vertebrate evolution and therefore exists in all modern vertebrate classes. The last decade has... (Review)
Review
The pituitary is a master endocrine gland that developed early in vertebrate evolution and therefore exists in all modern vertebrate classes. The last decade has transformed our view of this key organ. Traditionally, the pituitary has been viewed as a randomly organized collection of cells that respond to hypothalamic stimuli by secreting their content. However, recent studies have established that pituitary cells are organized in tightly wired large-scale networks that communicate with each other in both homo and heterotypic manners, allowing the gland to quickly adapt to changing physiological demands. These networks functionally decode and integrate the hypothalamic and systemic stimuli and serve to optimize the pituitary output into the generation of physiologically meaningful hormone pulses. The development of 3D imaging methods and transgenic models have allowed us to expand the research of functional pituitary networks into several vertebrate classes. Here we review the establishment of pituitary cell networks throughout vertebrate evolution and highlight the main perspectives and future directions needed to decipher the way by which pituitary networks serve to generate hormone pulses in vertebrates.
Topics: Animals; Endocrine Cells; Gonadotrophs; Humans; Hypothalamo-Hypophyseal System; Hypothalamus; Metabolic Networks and Pathways; Phylogeny; Pituitary Gland; Vertebrates
PubMed: 33584547
DOI: 10.3389/fendo.2020.619352 -
Medicina (Kaunas, Lithuania) Aug 2022Functioning gonadotroph adenomas (FGAs) are rare tumors, as the overwhelming majority of gonadotroph tumors are clinically silent. Literature is based on case reports... (Review)
Review
Functioning gonadotroph adenomas (FGAs) are rare tumors, as the overwhelming majority of gonadotroph tumors are clinically silent. Literature is based on case reports and small case series. Gonadotroph tumors are poorly differentiated and produce and secrete hormones inefficiently, but in exceptional cases, they cause clinical syndromes due to hypersecretion of intact gonadotropins. The clinical spectrum of endocrine dysfunction includes an exaggerated response of ovaries characterized as ovarian hyperstimulation syndrome (OHSS) in premenopausal females and adolescent girls, testicular enlargement in males, and isosexual precocious puberty in children. Transsphenoidal surgery and removal of tumor reduces hormonal hypersecretion, improves endocrine dysfunction, and provides tissue for further analysis. Medical therapies (somatostatin analogues, dopamine agonists, GnRH agonists/antagonists) are partially or totally ineffective in many cases, especially with respect to antitumor effect. This review aims to update recent literature on these rare functioning tumors and highlight their therapeutic management.
Topics: Adenoma; Adolescent; Child; Female; Follicle Stimulating Hormone; Gonadotrophs; Humans; Male; Pituitary Neoplasms; Somatostatin
PubMed: 36013538
DOI: 10.3390/medicina58081071 -
Frontiers in Endocrinology 2017The hypothalamic decapeptide gonadotropin-releasing hormone (GnRH), acting its receptors (GnRHRs) expressed in pituitary gonadotrophs, represents a critical molecule in... (Review)
Review
The hypothalamic decapeptide gonadotropin-releasing hormone (GnRH), acting its receptors (GnRHRs) expressed in pituitary gonadotrophs, represents a critical molecule in control of reproductive functions in all vertebrate species. GnRH-activated receptors regulate synthesis of gonadotropins in a frequency-dependent manner. The number of GnRHRs on the plasma membrane determines the responsiveness of gonadotrophs to GnRH and varies in relation to age, sex, and physiological status. This is achieved by a complex control that operates at transcriptional, translational, and posttranslational levels. This review aims to overview the mechanisms of GnRHR gene () transcription in mammalian gonadotrophs. In general, exhibits basal and regulated transcription activities. Basal transcription appears to be an intrinsic property of native and immortalized gonadotrophs that secures the presence of a sufficient number GnRHRs to preserve their functionality independently of the status of regulated transcription. On the other hand, regulated transcription modulates GnRHR expression during development, reproductive cycle, and aging. GnRH is crucial for regulated transcription in native gonadotrophs but is ineffective in immortalized gonadotrophs. In rat and mouse, both basal and GnRH-induced transcription rely primarily on the protein kinase C signaling pathway, with subsequent activation of mitogen-activated protein kinases. Continuous GnRH application, after a transient stimulation, shuts off regulated but not basal transcription, suggesting that different branches of this signaling pathway control transcription. Pituitary adenylate cyclase-activating polypeptide, but not activins, contributes to the regulated transcription utilizing the protein kinase A signaling pathway, whereas a mechanisms by which steroid hormones modulate transcription has not been well characterized.
PubMed: 28928715
DOI: 10.3389/fendo.2017.00221 -
Human Pathology Aug 2021Follicular cells (FCs) are thought to be agranular, non-hormone-producing stellate cells distributed throughout the adenohypophysis, occasionally arranged around...
Follicular cells (FCs) are thought to be agranular, non-hormone-producing stellate cells distributed throughout the adenohypophysis, occasionally arranged around colloid-filled follicles, and thought to be more prominent in the vicinity of necrosis and apoptotic cells. A distinct but similar cell type, the folliculostellate cell (FSC), is a sustentacular cell that is negative for keratins and stains for S100, GFAP, and SOX10. While several studies have examined FSCs in pituitary neuroendocrine tumors (PitNETs), the distribution and derivation of FCs in these lesions is unclear. We examined the presence and distribution of FCs in 104 PitNETs obtained by trans-sphenoidal surgery, using immunohistochemistry for keratins as well as the full complement of immunohistochemical stains for tumor characterization. The tumors included 9 somatotroph, 5 mammosomatotroph, 7 lactotroph, 7 immature PIT1-lineage, 2 acidophil stem cell, 17 corticotroph, 53 gonadotroph, 2 null cell, and 2 unusual plurihormonal tumors. CK-positive FCs were only identified in gonadotroph PitNETs and were found in 12 (23%) of those tumors; all other tumor types were negative for FCs. FCs express keratins identified by CAM5.2, AE1/AE3, CK18, and CK19 antibodies. FCs were identified scattered singly among hormone-producing neuroendocrine cells, in small clusters of 3-5 cells and surrounding colloid-filled follicles, as well as linearly along intratumoral blood vessels. Sequential stains showed that FCs express nuclear SF1 and GATA3, transcription factors of gonadotrophs, and multiplex immunohistochemistry confirmed colocalization of SF1 in the nucleus of keratin-positive FCs. In this series, FCs were exclusively found in gonadotroph PitNETs and occurred in 23% of those tumors. Co-expression of gonadotroph transcription factors in FCs supports the concept of cellular plasticity and transformation of neoplastic hormone-producing neuroendocrine cells to FCs. Further studies are required to determine if and why gonadotrophs alone undergo this transformation, the function of these cells and whether they have prognostic value.
Topics: Biomarkers, Tumor; Cell Plasticity; Humans; Immunohistochemistry; Neuroendocrine Tumors; Phenotype; Pituitary Neoplasms; Prognosis; Retrospective Studies
PubMed: 33991528
DOI: 10.1016/j.humpath.2021.05.002 -
Current Opinion in Pharmacology Oct 2022Pituitary gonadotrophs play a key role in reproductive functions by secreting luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The LH secretory activity... (Review)
Review
Pituitary gonadotrophs play a key role in reproductive functions by secreting luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The LH secretory activity of gonadotroph is controlled by hypothalamic gonadotropin-releasing hormone (GnRH) via GnRH receptors and is accompanied by only minor effects on high basal Lhb gene expression. The secretory profiles of GnRH and LH are highly synchronized, with the latter reflecting a depletion of prestored LH in secretory vesicles by regulated exocytosis. In contrast, FSH is predominantly released by constitutive exocytosis, and secretory activity reflects the kinetics of Fshb gene expression controlled by GnRH, activin, and inhibin. Here is a review of recent data to improve the understanding of multiple patterns of gonadotroph gene expression and hormone secretion.
Topics: Activins; Follicle Stimulating Hormone; Gene Expression; Gonadotrophs; Gonadotropin-Releasing Hormone; Humans; Inhibins; Luteinizing Hormone; Receptors, LHRH
PubMed: 35994915
DOI: 10.1016/j.coph.2022.102274 -
Cancers Dec 2022The pituitary gland is one of the most cellularly diverse regions of the brain. Recent advancements in transcriptomic biology, such as single-cell RNA sequencing, bring... (Review)
Review
The pituitary gland is one of the most cellularly diverse regions of the brain. Recent advancements in transcriptomic biology, such as single-cell RNA sequencing, bring an unprecedented glimpse into the molecular composition of the pituitary, both in its normal physiological state and in disease. Deciphering the normal pituitary transcriptomic signatures provides a better insight into the ontological origin and development of five types of endocrine cells, a process involving complex cascades of transcription factors that are still being established. In parallel with these observations about normal pituitary development, recent transcriptomic findings on pituitary neuroendocrine tumors (PitNETs) demonstrate both preservations and changes in transcription factor expression patterns compared to those seen during gland development. Furthermore, recent studies also identify differentially expressed genes that drive various tumor behaviors, including hormone hypersecretion and tumor aggression. Understanding the comprehensive multiomic profiles of PitNETs is essential in developing molecular profile-based therapies for PitNETs not curable with current treatment modalities and could eventually help align PitNETs with the breakthroughs being made in applying precision medicine to other tumors.
PubMed: 36612109
DOI: 10.3390/cancers15010110