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

Cell Reports Medicine
Derek K SmithAndrew S Peterson

Abstract

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.

Citations

Apr 4, 2021·Pharmaceuticals·Tyler SniegowskiVadivel Ganapathy

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Datasets Mentioned

BETA
GSE142234
AB183734
AB92517
AB72717

Methods Mentioned

BETA
exome sequencing
RNA-seq
fluorescence-activated cell sorting
biopsies
exome-seq
transgenic
RNA assay
fluorescence imaging

Software Mentioned

STAR aligner
nCounter Analysis System
Subread
BWA
Nanostring
Ensembl
Strelka
Partek
Trimmomatic
MATLAB

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