An update on genetically engineered mouse models of pancreatic neuroendocrine neoplasms

Abstract

Pancreatic neuroendocrine neoplasms (PanNENs) are rare and clinically challenging entities. At the molecular level, PanNENs’ genetic profile is well-characterized but there is limited knowledge regarding the contribution of the newly identified genes to tumor initiation and progression. Genetically engineered mouse models (GEMMs) are the most versatile tool for studying the plethora of genetic variations influencing PanNENs etiopathogenesis and behavior over time. In this review, we present the state-of-the-art of the most relevant PanNEN GEMMs available and correlate their findings with the human neoplasms’ counterparts. We discuss the historic GEMMs as the most used and with higher translational utility models. GEMMs with Men1 and glucagon receptor gene germline alterations stand out as the most faithful models in recapitulating human disease; RIP-Tag models are unique models of early onset, highly vascularized, invasive carcinomas. We also include a section of the most recent GEMMs that evaluate pathways related to cell cycle and apoptosis, Pi3k/Akt/mTOR and Atrx/Daxx. For the latter, their tumorigenic effect is heterogeneous. In particular, for Atrx/Daxx, we will require more in-depth studies to evaluate their contribution; even though they are prevalent genetic events in PanNENs, they have low/inexistent tumorigenic capacity per se in GEMMs. Researchers planning to use GEMMs can find a roadmap of the main clinical features in this review, presented as a guide that summarizes the chief milestones achieved. We identify pitfalls to overcome, concerning the novel designs and standardization of results, so that future models can replicate human disease more closely.

An Insight on Functioning Pancreatic Neuroendocrine Neoplasms

“…The basic and preclinical research allowed us to better characterize the main pathways underlying the functioning PanNENs. Among all mice models [171], it is worth mentioning the RIP-Tag and menin-deficient mice, which contributed to test the efficacy of pasireotide, sunitinib and mTOR inhibitors [172][173][174], and a new mouse model harboring thymidylate synthase (TS) overexpression and Men1 inactivation in pancreatic islet cells (hTS/Men1 −/ − ). This mouse model allowed us to identify a crucial dualism between these two proteins in exacerbating PanNETs progression [175].…”

Generation of an Obese Diabetic Mouse Model upon Conditional Atrx Disruption

“…Genetically engineered mouse models (GEMMs) are the most powerful tool to study the PanNETs' multistep tumourigenic pathway, regarding tumour initiation and progression, under an immune-competent phenotype [33]. Despite the increasing acceptance of the chromatin remodellers' utility as prognostic markers in the context of human PanNETs, their specific contribution to PanNET tumourigenesis is still underexplored.…”