Two well-differentiated pancreatic neuroendocrine tumor mouse models

Chung Wong, Laura H. Tang, Christian Davidson, Evan Vosburgh, Wenjin Chen, David J. Foran, Daniel A. Notterman, Arnold J. Levine, Eugenia Y. Xu

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is a genetic syndrome in which patients develop neuroendocrine tumors (NETs), including pancreatic neuroendocrine tumors (PanNETs). The prolonged latency of tumor development in MEN1 patients suggests a likelihood that other mutations cooperate with Men1 to induce PanNETs. We propose that Pten loss combined with Men1 loss accelerates tumorigenesis. To test this, we developed two genetically engineered mouse models (GEMMs)—MPR (Men1flox/floxPtenflox/flox RIP-Cre) and MPM (Men1flox/floxPtenflox/flox MIP-Cre) using the Cre-LoxP system with insulin-specific biallelic inactivation of Men1 and Pten. Cre in the MPR mouse model was driven by the transgenic rat insulin 2 promoter while in the MPM mouse model was driven by the knock-in mouse insulin 1 promoter. Both mouse models developed well-differentiated (WD) G1/G2 PanNETs at a much shorter latency than Men1 or Pten single deletion alone and exhibited histopathology of human MEN1-like tumor. The MPR model, additionally, developed pituitary neuroendocrine tumors (PitNETs) in the same mouse at a much shorter latency than Men1 or Pten single deletion alone as well. Our data also demonstrate that Pten plays a role in NE tumorigenesis in pancreas and pituitary. Treatment with the mTOR inhibitor rapamycin delayed the growth of PanNETs in both MPR and MPM mice, as well as the growth of PitNETs, resulting in prolonged survival in MPR mice. Our MPR and MPM mouse models are the first to underscore the cooperative roles of Men1 and Pten in cancer, particularly neuroendocrine cancer. The early onset of WD PanNETs mimicking the human counterpart in MPR and MPM mice at 7 weeks provides an effective platform for evaluating therapeutic opportunities for NETs through targeting the MENIN-mediated and PI3K/AKT/mTOR signaling pathways.

Original languageEnglish (US)
Pages (from-to)269-283
Number of pages15
JournalCell Death and Differentiation
Volume27
Issue number1
DOIs
StatePublished - Jan 1 2020

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Wong, C., Tang, L. H., Davidson, C., Vosburgh, E., Chen, W., Foran, D. J., Notterman, D. A., Levine, A. J., & Xu, E. Y. (2020). Two well-differentiated pancreatic neuroendocrine tumor mouse models. Cell Death and Differentiation, 27(1), 269-283. https://doi.org/10.1038/s41418-019-0355-0