Two well-differentiated pancreatic neuroendocrine tumor mouse models
Authors: Laura H Tang
Chung Wong
Evan Vosburgh
Daniel A Notterman
Arnold J Levine
Christian Davidson
Wenjin Chen
Eugenia Y Xu
David J Foran
Journal: Cell Death and Differentiation (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Multiple endocrine neoplasia type 1; MEN1; neuroendocrine tumors; Pancreatic neuroendocrine tumors; Pten loss
Affiliations: Raymond and Beverly Sackler Foundation Laboratory, New Brunswick, NJ, 08901, USA., Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA., Department of Pathology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA., Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08903, USA., Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA., School of Natural Sciences, Institute for Advanced Study, Princeton, NJ, 08540, USA., Raymond and Beverly Sackler Foundation Laboratory, New Brunswick, NJ, 08901, USA. .

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/flox Ptenflox/flox RIP-Cre) and MPM (Men1flox/flox Ptenflox/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. 

Retracted: No

PubPeer comments:
 Figure 3A appears to have a repeated band. Could the authors please post the original scans? See also: https: pubpeer.com search?q=authors%3A%22Arnold+J.+Levine%22 *** Original https: imgur.com a 4jMthTn *** Inverse https: imgur.com a fwjHQvB , 
 #1 https: drive.google.com file d 1O086wXDXpVM2CK0RkYrnBIqgiahNr_as view?usp=sharing Thanks for careful reading. Here s the figure 3 with correct total AKT. ,