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GCGR Loss-of-Function Mutations Promote Amino Acid-Dependent Pancreatic Neuroendocrine Tumor Initiation from a Subpopulation of Alpha Cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE142234 | GEO | 2020/05/28

REPOSITORIES: GEO

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GCGR Loss-of-Function Mutations Promote Amino Acid-Dependent Pancreatic Neuroendocrine Tumor Initiation from a Subpopulation of Alpha Cells [exome-seq]

Project description:Study gene expression changes in alpha cells and tumors from GCGR knockout mice

2020-05-29 | GSE142231 | GEO

GCGR Loss-of-Function Mutations Promote Amino Acid-Dependent Pancreatic Neuroendocrine Tumor Initiation from a Subpopulation of Alpha Cells [bulk RNA-seq]

Project description:Study gene expression changes in alpha cells and tumors from GCGR knockout mice

2020-05-29 | GSE142232 | GEO

GCGR Loss-of-Function Mutations Promote Amino Acid-Dependent Pancreatic Neuroendocrine Tumor Initiation from a Subpopulation of Alpha Cells [single-cell RNA-seq]

Project description:Evaluating cell subpopulations in mouse pancreatic islets and pancreatic tumors

2020-05-29 | GSE142233 | GEO

GCGR Loss-of-Function Mutations Promote Amino Acid-Dependent Pancreatic Neuroendocrine Tumor Initiation from a Subpopulation of Alpha Cells

Project description:GCGR Loss-of-Function Mutations Promote Amino Acid-Dependent Pancreatic Neuroendocrine Tumor Initiation from a Subpopulation of Alpha Cells

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GCGR Loss-of-Function Mutations Promote Amino Acid-Dependent Pancreatic Neuroendocrine Tumor Initiation from a Subpopulation of Alpha Cells [exome-seq]

Project description:GCGR Loss-of-Function Mutations Promote Amino Acid-Dependent Pancreatic Neuroendocrine Tumor Initiation from a Subpopulation of Alpha Cells [exome-seq]

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GCGR Loss-of-Function Mutations Promote Amino Acid-Dependent Pancreatic Neuroendocrine Tumor Initiation from a Subpopulation of Alpha Cells [bulk RNA-seq]

Project description:GCGR Loss-of-Function Mutations Promote Amino Acid-Dependent Pancreatic Neuroendocrine Tumor Initiation from a Subpopulation of Alpha Cells [bulk RNA-seq]

| PRJNA596266 | ENA

GCGR Loss-of-Function Mutations Promote Amino Acid-Dependent Pancreatic Neuroendocrine Tumor Initiation from a Subpopulation of Alpha Cells [single-cell RNA-seq]

Project description:GCGR Loss-of-Function Mutations Promote Amino Acid-Dependent Pancreatic Neuroendocrine Tumor Initiation from a Subpopulation of Alpha Cells [single-cell RNA-seq]

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Elevated Serum Amino Acids Induce a Subpopulation of Alpha Cells to Initiate Pancreatic Neuroendocrine Tumor Formation.

Project description:The cellular origin of sporadic pancreatic neuroendocrine tumors (PNETs) is obscure. Hormone expression suggests that these tumors arise from glucagon-producing alpha cells or insulin-producing β cells, but instability in hormone expression prevents linage determination. We utilize loss of hepatic glucagon receptor (GCGR) signaling to drive alpha cell hyperproliferation and tumor formation to identify a cell of origin and dissect mechanisms that drive progression. Using a combination of genetically engineered Gcgr knockout mice and GCGR-inhibiting antibodies, we show that elevated plasma amino acids drive the appearance of a proliferative population of SLC38A5+ embryonic progenitor-like alpha cells in mice. Further, we characterize tumors from patients with rare bi-allelic germline GCGR loss-of-function variants and find prominent tumor-cell-associated expression of the SLC38A5 paralog SLC7A8 as well as markers of active mTOR signaling. Thus, progenitor cells arise from adult alpha cells in response to metabolic signals and, when inductive signals are chronically present, drive tumor initiation.

| S-EPMC7659536 | biostudies-literature

Deleterious mutation V369M in the mouse GCGR gene causes abnormal plasma amino acid levels indicative of a possible liver-α-cell axis.

Project description:Glucagon plays an important role in glucose homeostasis and amino acid metabolism. It regulates plasma amino acid levels which in turn modulate glucagon secretion from the pancreatic α-cell, thereby establishing a liver-α-cell axis described recently. We reported previously that the knock-in mice bearing homozygous V369M substitution (equivalent to a naturally occurring mutation V368M in the human glucagon receptor, GCGR) led to hypoglycemia with improved glucose tolerance. They also exhibited hyperglucagonemia, pancreas enlargement and α-cell hyperplasia. Here, we investigated the effect of V369M/V368M mutation on glucagon-mediated amino acid metabolism. It was found that GcgrV369M+/+ mice displayed increased plasma amino acid levels in general, but significant accumulation of the ketogenic/glucogenic amino acids was observed in animals fed with a high-fat diet (HFD), resulting in deleterious metabolic consequence characteristic of α-cell proliferation and hyperglucagonemia.

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Hypothalamic tumor necrosis factor-alpha converting enzyme mediates excitatory amino acid-dependent neuron-to-glia signaling in the neuroendocrine brain.

Project description:Glial erbB1 receptors play a significant role in the hypothalamic control of female puberty. Activation of these receptors by transforming growth factor alpha (TGFalpha) results in production of prostaglandin E2, which then stimulates luteinizing hormone releasing hormone (LHRH) neurons to secrete LHRH, the neuropeptide controlling sexual development. Glutamatergic neurons set in motion this glia-to-neuron signaling pathway by transactivating erbB1 receptors via coactivation of AMPA receptors (AMPARs) and metabotropic glutamate receptors (mGluRs). Because the metalloproteinase tumor necrosis factor alpha converting enzyme (TACE) releases TGFalpha from its transmembrane precursor before TGFalpha can bind to erbB1 receptors, we sought to determine whether TACE is required for excitatory amino acids to activate the TGFalpha-erbB1 signaling module in hypothalamic astrocytes, and thus facilitate the advent of puberty. Coactivation of astrocytic AMPARs and mGluRs caused extracellular Ca2+ influx, a Ca2+/protein kinase C-dependent increase in TACE-like activity, and enhanced release of TGFalpha. Within the hypothalamus, TACE is most abundantly expressed in astrocytes of the median eminence (ME), and its enzymatic activity increases selectively in this region at the time of the first preovulatory surge of gonadotropins. ME explants respond to stimulation of AMPARs and mGluRs with LHRH release, and this response is prevented by blocking TACE activity. In vivo inhibition of TACE activity targeted to the ME delayed the age at first ovulation, indicating that ME-specific changes in TACE activity are required for the normal timing of puberty. These results suggest that TACE is a component of the neuron-to-glia signaling process used by glutamatergic neurons to control female sexual development.

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