Animal models of MEN1

Abstract

Animal models of cancer have been instrumental in advancing our understanding of the biology of tumor initiation and progression, in studying gene function and in performing preclinical studies aimed at testing novel therapies. Several animal models of the MEN1 syndrome have been generated in different organisms by introducing loss-of-function mutations in the orthologues of the human MEN1 gene. In this review, we will discuss MEN1 and MEN1-like models in Drosophila, mice and rats. These model systems with their specific advantages and limitations have contributed to elucidate the function of Menin in tumorigenesis, which turned out to be remarkably conserved from flies to mammals, as well as the biology of the disease. Mouse models of MEN1 closely resemble the human disease in terms of tumor spectrum and associated hormonal changes, although individual tumor frequencies are variable. Rats affected by the MENX (MEN1-like) syndrome share some features with MEN1 patients albeit they bear a germline mutation in Cdkn1b (p27) and not in Men1. Both Men1-knockout mice and MENX rats have been exploited for therapy-response studies testing novel drugs for efficacy against neuroendocrine tumors (NETs) and have provided promising leads for novel therapies. In addition to presenting well-established models of MEN1, we also discuss potential models which, if implemented, might broaden even further our knowledge of neuroendocrine tumorigenesis. In the future, patient-derived xenografts in zebrafish or mice might allow us to expand the tool-box currently available for preclinical studies of MEN1-associated tumors.

Two well-differentiated pancreatic neuroendocrine tumor mouse models

“…The human and mouse genes share a highly conserved genomic structure with 89% nucleotide sequence homology and 97% amino acid sequence homology, respectively [22]. Mouse strains with defective Men1 possess remarkable phenotypic and histological overlap with the human MEN1 syndrome.…”

Mouse models of endocrine tumors

“…MEN1 syndrome is mostly associated to the appearance of pancreatic, parathyroid and pituitary tumors (Thakker 2014). The mouse models developed to study this syndrome are exclusively based on mutations in Men1 gene (Mohr & Pellegata 2017) and, therefore, the putative use of PDX models could represent a substantial advance in the near future (Table 1). Remarkably, all these mouse models of MEN1 syndrome show a remarkable overlap with the human syndrome in terms of pathologically relevant features, as recently reviewed (Mohr & Pellegata 2017), and therefore represent ideal models to explore different aspects of this endocrine syndrome.…”

“…Indeed, this heterogeneity, together with the limited incidence of some of these tumor types, drastically hampers the possibility of implementing high-scale translational and clinical studies. In this scenario, mouse models have emerged as a powerful and essential tool in basic and translational tumor biology research (Day et al 2015, Gengenbacher et al 2017, Kersten et al 2017, specially in the case of endocrine and neuroendocrine tumors (Basham et al 2016, Lines et al 2016, Mohr & Pellegata 2017, Vitale et al 2017. There are numerous examples of breakthrough discoveries in preclinical mouse tumor models that paved the way for clinical application in humans, such as the first demonstration of the efficacy of immune checkpoint blockade for the treatment of tumor pathologies (Leach et al 1996).…”

Happy 20th anniversary MEN1: from positional cloning to gene function restoration

“…This aspect is further highlighted by an outstanding review provided by Hermine Mohr and Natalia Pellegata. These authors bring us up-to-date on the available animal models for MEN1 research and provide us with their vision for future developments (Mohr & Pellegata 2017).…”

“…The review articles cover the broad range of MEN1 syndrome and focus on the clinical (Manoharan et al 2017, Marini et al 2017, van Leeuwaarde et al 2017, translational (Agarwal 2017, Alrezk et al 2017 and basic scientific , Feng et al 2017, Mohr & Pellegata 2017 aspects; therefore, they provide a comprehensive update on MEN1. We are delighted that several of the scientists that pioneered MEN1 research provided their expertise to this special issue.…”