Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
University Hospital Tübingen, Internal Medicine VIII, Tübingen 72076, Germany.
Cell Rep Med. 2020 Aug 25;1(5):100058. doi: 10.1016/j.xcrm.2020.100058.
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 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 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.
散发性胰腺神经内分泌肿瘤（PNETs）的细胞起源尚不清楚。激素表达表明这些肿瘤来源于胰高血糖素产生的α细胞或胰岛素产生的β细胞，但激素表达的不稳定性阻止了谱系的确定。我们利用肝源性胰高血糖素受体（GCGR）信号的丧失来驱动α细胞的过度增殖和肿瘤形成，以确定起始细胞并剖析驱动进展的机制。我们使用基因工程敲除小鼠和 GCGR 抑制抗体的组合，表明升高的血浆氨基酸驱动 SLC38A5 胚胎祖细胞样α细胞的增殖群体在小鼠中出现。此外，我们对来自具有罕见双等位基因种系功能丧失变异的患者的肿瘤进行了表征，发现 SLC38A5 旁系物 SLC7A8 以及活跃的 mTOR 信号标志物在肿瘤细胞中显著表达。因此，祖细胞是在代谢信号的作用下从成熟的α细胞中产生的，而当诱导信号持续存在时，会驱动肿瘤的发生。
