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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

| PRJNA596261 | ENA

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]

| PRJNA596267 | ENA

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]

| PRJNA596265 | ENA

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.

| S-EPMC8173527 | biostudies-literature

Amino Acid Transporter Slc38a5 Controls Glucagon Receptor Inhibition-Induced Pancreatic α Cell Hyperplasia in Mice.

Project description:Glucagon supports glucose homeostasis by stimulating hepatic gluconeogenesis, in part by promoting the uptake and conversion of amino acids into gluconeogenic precursors. Genetic disruption or pharmacologic inhibition of glucagon signaling results in elevated plasma amino acids and compensatory glucagon hypersecretion involving expansion of pancreatic α cell mass. Recent findings indicate that hyperaminoacidemia triggers pancreatic α cell proliferation via an mTOR-dependent pathway. We confirm and extend these findings by demonstrating that glucagon pathway blockade selectively increases expression of the sodium-coupled neutral amino acid transporter Slc38a5 in a subset of highly proliferative α cells and that Slc38a5 controls the pancreatic response to glucagon pathway blockade; most notably, mice deficient in Slc38a5 exhibit markedly decreased α cell hyperplasia to glucagon pathway blockade-induced hyperaminoacidemia. These results show that Slc38a5 is a key component of the feedback circuit between glucagon receptor signaling in the liver and amino-acid-dependent regulation of pancreatic α cell mass in mice.

| S-EPMC8206958 | biostudies-literature

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