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

Shinta Kobayashi,Laura H Tang,Richard Clausen,Chris R Harris,Yi-Chieh Nancy Du,Tanupriya Contractor,Evan Vosburgh

doi:10.1038/s41389-019-0127-1

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.

Highlights

Neuroendocrine cells function by secreting hormones in response to neurological or metabolic stimuli
RT2 AB6F1 mice were generated by mating females from the inbred A/J genetic background to male RT2 bred into a C57Bl/6 (B6) mice, which have an inbred C57Bl/6 J genetic background[12]
Pancreatic tumors were produced that were neuroendocrine tumors upon pathological examination, albeit less welldifferentiated than the pancreatic neuroendocrine tumors (PanNETs) found in most patients

Summary

Introduction

Neuroendocrine cells function by secreting hormones in response to neurological or metabolic stimuli. The insulin-producing beta cells of the pancreas are the bestknown example of neuroendocrine cells, because beta cell defects can result in diabetes. Neuroendocrine cells are found in many other sites of the body, including the pituitary, thyroid, parathyroid, small and large intestine. In order to maintain proper hormone balance, neuroendocrine cells are under tight growth regulation. Neuroendocrine cells can become transformed and develop into neuroendocrine tumors. Transformation of pancreatic beta cells results in pancreatic neuroendocrine tumors (PanNETs). PanNETs are the second most common tumors of the pancreas, with an incidence of 1 per 200,000, and the incidence of PanNETs has been increasing rapidly[1].

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