PMID- 31160716 OWN - NLM STAT- MEDLINE DCOM- 20210402 LR - 20211030 IS - 1476-5403 (Electronic) IS - 1350-9047 (Print) IS - 1350-9047 (Linking) VI - 27 IP - 1 DP - 2020 Jan TI - Two well-differentiated pancreatic neuroendocrine tumor mouse models. PG - 269-283 LID - 10.1038/s41418-019-0355-0 [doi] AB - 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 (Men1(flox/flox) Pten(flox/flox) RIP-Cre) and MPM (Men1(flox/flox) Pten(flox/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. FAU - Wong, Chung AU - Wong C AD - Raymond and Beverly Sackler Foundation Laboratory, New Brunswick, NJ, 08901, USA. AD - Regeneron Inc., Tarrytown, NY, 10591, USA. FAU - Tang, Laura H AU - Tang LH AD - Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA. FAU - Davidson, Christian AU - Davidson C AD - Department of Pathology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA. FAU - Vosburgh, Evan AU - Vosburgh E AUID- ORCID: 0000-0002-1728-7787 AD - Raymond and Beverly Sackler Foundation Laboratory, New Brunswick, NJ, 08901, USA. AD - Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08903, USA. AD - Department of Medicine, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08901, USA. AD - Department of Medicine, Yale University School of Medicine, New Haven, CT, 06510, USA. FAU - Chen, Wenjin AU - Chen W AD - Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08903, USA. AD - Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08901, USA. FAU - Foran, David J AU - Foran DJ AD - Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08903, USA. AD - Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08901, USA. FAU - Notterman, Daniel A AU - Notterman DA AD - Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA. FAU - Levine, Arnold J AU - Levine AJ AD - School of Natural Sciences, Institute for Advanced Study, Princeton, NJ, 08540, USA. FAU - Xu, Eugenia Y AU - Xu EY AD - Raymond and Beverly Sackler Foundation Laboratory, New Brunswick, NJ, 08901, USA. exu@princeton.edu. AD - Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08903, USA. exu@princeton.edu. AD - Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08901, USA. exu@princeton.edu. AD - Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA. exu@princeton.edu. LA - eng GR - P30 CA072720/CA/NCI NIH HHS/United States GR - P30 CA008748/CA/NCI NIH HHS/United States GR - P2C HD047879/HD/NICHD NIH HHS/United States GR - UG3 CA225021/CA/NCI NIH HHS/United States GR - UL1 TR003017/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190603 PL - England TA - Cell Death Differ JT - Cell death and differentiation JID - 9437445 RN - 0 (Antibiotics, Antineoplastic) RN - 0 (Men1 protein, mouse) RN - 0 (Proto-Oncogene Proteins) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (Pten protein, mouse) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Antibiotics, Antineoplastic/therapeutic use MH - Carcinogenesis MH - *Disease Models, Animal MH - Gene Deletion MH - *Mice MH - Neuroendocrine Tumors/drug therapy/metabolism/pathology MH - PTEN Phosphohydrolase/genetics/*physiology MH - Pancreatic Neoplasms/drug therapy/metabolism/pathology MH - Proto-Oncogene Proteins/genetics/*physiology MH - Sirolimus/therapeutic use PMC - PMC7206057 COIS- The authors declare that they have no conflict of interest. EDAT- 2019/06/05 06:00 MHDA- 2021/04/07 06:00 PMCR- 2019/06/03 CRDT- 2019/06/05 06:00 PHST- 2019/01/18 00:00 [received] PHST- 2019/05/07 00:00 [accepted] PHST- 2019/04/26 00:00 [revised] PHST- 2019/06/05 06:00 [pubmed] PHST- 2021/04/07 06:00 [medline] PHST- 2019/06/05 06:00 [entrez] PHST- 2019/06/03 00:00 [pmc-release] AID - 10.1038/s41418-019-0355-0 [pii] AID - 355 [pii] AID - 10.1038/s41418-019-0355-0 [doi] PST - ppublish SO - Cell Death Differ. 2020 Jan;27(1):269-283. doi: 10.1038/s41418-019-0355-0. Epub 2019 Jun 3.