Alleles of Insm1 determine whether RIP1-Tag2 mice produce insulinomas or nonfunctioning pancreatic neuroendocrine tumors

Abstract The two most common types of pancreatic neuroendocrine tumors (PanNETs) are insulinomas and nonfunctioning PanNETs (NF-PanNETs). Insulinomas are small, rarely metastatic tumors that secrete high amounts of insulin, and nonfunctioning PanNETs are larger tumors that are frequently metastatic but that do not secrete hormones. Insulinomas are modeled by the highly studied RIP1-Tag2 (RT2) transgenic mice when bred into a C57Bl/6 (B6) genetic background (also known as RT2 B6 mice). But there has been a need for an animal model of nonfunctioning PanNETs, which in the clinic are a more common and severe disease. Here we show that when bred into a hybrid AB6F1 genetic background, RT2 mice make nonfunctioning PanNETs. Compared to insulinomas produced by RT2 B6 mice, the tumors produced by RT2 AB6F1 mice were larger and more metastatic, and the animals did not suffer from hypoglycemia or hyperinsulinemia. Genetic crosses revealed that a locus in mouse chromosome 2qG1 was linked to liver metastasis and to lack of insulin production. This locus was tightly linked to the gene encoding Insm1 , a beta cell transcription factor that was highly expressed in human insulinomas but unexpressed in other types of PanNETs due to promoter hypermethylation. Insm1 -deficient human cell lines expressed stem cell markers, were more invasive in vitro, and metastasized at higher rates in vivo when compared to isogenic Insm1 -expressing cell lines. These data demonstrate that expression of Insm1 can determine whether a PanNET is a localized insulinoma or a metastatic nonfunctioning tumor.