Conditional deletion of p53 and Rb in the renin-expressing compartment of the pancreas leads to a highly penetrant metastatic pancreatic neuroendocrine carcinoma

Abstract

Efforts to model human pancreatic neuroendocrine tumors (PanNET) in animals have been moderately successful, with minimal evidence for glucagonomas or metastatic spread. The renin gene while classically associated with expression in the kidney is also expressed in many other extra-renal tissues including the pancreas. To induce tumorigenesis within renin specific tissues, floxed alleles of p53 and Rb were selectively abrogated using Cre-recombinase driven by the renin promoter. The primary neoplasm generated is a highly metastatic islet cell carcinoma of the pancreas. Lineage tracing identifies descendants of renin-expressing cells as pancreatic alpha cells despite a lack of active renin expression in the mature pancreas. Both primary and metastatic tumors express high levels of glucagon, furthermore an increased level of glucagon is found in the serum identifying the pancreatic cancer as a functional glucagonoma. This new model is highly penetrant and exhibits robust frequency of metastases to lymph nodes and liver, mimicking human disease and provides a useful platform for better understanding pancreatic endocrine differentiation and development, as well as islet cell carcinogenesis. The use of fluorescent reporters for lineage tracing of the cells contributing to disease initiation and progression provides a unique opportunity to dissect the timeline of disease, examining mechanisms of the metastatic process, as well as recovering primary and metastatic cells for identifying co-operating mutations that are necessary for progression of disease.

EPB41L5 is Associated With the Metastatic Potential of Low-grade Pancreatic Neuroendocrine Tumors

“…Research has focused on distinguishing GAs that drive the biological behavior of PNETs from those that drive PECAs (18)(19)(20)(21)(22)(23). GAs in genes involved in chromatin remodeling, such as MEN1, DAXX, and ATRX, as well as those in phosphatase and tensin homolog (PTEN) loss, have been found to be enriched in G1, G2, and G3 PNETs, whereas PECAs have been determined to be enriched in GAs that lead to the inactivation of TP53 and/or RB1 and to EMT (5, 19,20,[24][25][26][27][28][29]. Here, we propose EPB41L5 as a potential new biomarker for LG-PNET with metastatic potential.…”

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“…The only other MYCN-driven animal model of MYCN-induced PanNETs was described in zebrafish, yet the developing tumors were similar to human insulinomas [32]. PanNETs expressing glucagon have also been described in mice with a deletion of the glucagon receptor [33], or with a conditional deletion of p53 and Rb [15].…”

“…Those that are syndromic may produce clinical conditions, such as the insulinoma syndrome, gastrinoma syndrome (also known as Zollinger-Ellison syndrome), glucagonoma syndrome and VIPoma syndrome (also known as Verner-Morrison syndrome, ordered by declining frequency, for review see [12], [13]). Until recently, the existing mouse models for glucagonoma were established by conditional deletion of tumor-suppressor genes including MEN1 or by combined loss of p53 and Rb [14,15]. These model systems used insulin-promoter or renin-promoter driven expression of Cre recombinase, respectively, to induce target gene deletion.…”

Animal models of spontaneous pancreatic neuroendocrine tumors

“…The tumors grow rapidly and appear aggressive; by 6 months, ~40% of mice harbor liver metastasis, and by 8 months, all of the mice died apparently due to tumor burden and hyperglucagonemia. Interestingly, renin expression is found in M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 10 embryonic α cells, explaining the emergence of glucagonomas (Glenn et al, 2014). The glucagonomas in this model closely mimic some human sporadic glucagonomas and may be useful for studying therapeutic response of human glucagonomas to targeted therapies.…”