Abstract 478: A mouse model for highly metastatic, nonfunctioning pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors are generally classified as functioning or nonfunctioning. Patients with functioning tumors can have severe hypoglycemia because their tumors express high amounts of insulin as well as chromogranin A; fortunately, these tumors are seldom metastatic. Patients with nonfunctioning tumors express high amounts of chromogranin A but little insulin; unfortunately these tumors are highly metastatic to the liver. Nonfunctioning tumors are more common, and a more severe health issue. The highly studied RT2 B6 mouse, in which the SV40 T antigen is expressed from an insulin promoter in an inbred C57Bl/6 genetic background, is a model for functioning pancreatic neuroendocrine tumors: liver metastasis is uncommon in RT2 B6 mice, which are very hypoglycemic and often die when tumors are very small. We have changed the genetic background and are studying RT2 AB6F1 hybrid mice, which have a C57Bl/6 father and a mother from an A/J inbred background. RT2 AB6F1 mice are much less hypoglycemic, and these mice develop liver metastasis with high frequency. We have mated the hybrid AB6F1 mice to their littermates in order to map metastasis genes by F2 analysis, and have discovered that a locus at mouse chromosome 2qG1 links tightly to liver metastasis. One gene within this locus, InsM1, is less expressed in the primary tumors of mice with liver metastatic disease. InsM1 is also less expressed in primary tumors from humans with liver metastatic disease. Previous studies of InsM1 have shown that this protein maintains the differentiated status of pancreatic beta cells. We find that tumors from mice with low expression of InsM1 also express lower amounts of several distinctive markers of differentiated beta cells, but higher amounts of several markers of liver cells. These data suggest that dedifferentiation to stem cells, which can then redifferentiate to other cell types such as liver cells, promotes metastasis of pancreatic beta cell tumors. Intratumoral expression of liver markers may be a useful predictor of metastatic disease in these patients. Dedifferentiation of mature beta cells is also a mechanism by which type 2 diabetes occurs, so there may be similarities between these two diseases. Citation Format: Tanupriya Contractor, Shinta Kobayashi, Richard Clausen, Edaise da Silva, Laura Tang, Chang Chan, Chris R. Harris. A mouse model for highly metastatic, nonfunctioning pancreatic neuroendocrine tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 478.