Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is believed to arise through a multistep model comprised of putative precursor lesions known as pancreatic intraepithelial neoplasia (PanIN). Recent genetically engineered mouse models of PDAC demonstrate a comparable morphologic spectrum of murine PanIN (mPanIN) lesions. The histogenesis of PanIN and PDAC in both mice and men remains controversial. The most faithful genetic models activate an oncogenic Kras G12D knockin allele within the pdx1-or ptf1a/p48-expression domain of the entire pancreatic anlage during development, thus obscuring the putative cell(s)-of-origin from which subsequent mPanIN lesions arise. In our study, activation of this knockin Kras G12D allele in the Elastase-and Mist1-expressing mature acinar compartment of adult mice resulted in the spontaneous induction of mPanIN lesions of all histological grades, although invasive carcinomas per se were not seen. We observed no requirement for concomitant chronic exocrine injury in the induction of mPanIN lesions from the mature acinar cell compartment. The acinar cell derivation of the mPanINs was established through lineage tracing in reporter mice, and by microdissection of lesional tissue demonstrating Cre-mediated recombination events. In contrast to the uniformly penetrant mPanIN phenotype observed following developmental activation of Kras G12D in the Pdx1-expressing progenitor cells, the Pdx1-expressing population in the mature pancreas (predominantly islet ␤ cells) appears to be relatively resistant to the effects of oncogenic Kras. We conclude that in the appropriate genetic context, the differentiated acinar cell compartment in adult mice retains its susceptibility for spontaneous transformation into mPanIN lesions, a finding with potential relevance vis-à -vis the origins of PDAC.lineage tracing ͉ transdifferentiation ͉ precursor lesions ͉ pancreatic cancer

Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing

“…The identity of the cell types capable of giving rise to pancreatic cancer is an area of active investigation and considerable debate (Guerra et al 2007;Habbe et al 2008;Gidekel Friedlander et al 2009;Kopp et al 2012;Puri et al 2015). The Adeno-Cre and Lenti-Cre that we used in this study mostly had ubiquitous promoters (CMV and PGK, respectively), which led to recombination in acinar, ductal, and islet cells in the pancreas, although Lenti- Cre had a very strong preference for acinar cells (Supplemental Fig.…”

“…4B). While a vast majority of pancreatic cancer studies have used non-cell type-specific promoters to drive Cre, models using transgenic and knock-in Cre(ER) alleles to enable cell type-specific expression of oncogenic Kras and tumor suppressor loss have been used to identify cells that possess the ability to give rise to PDAC (Guerra et al 2007;Habbe et al 2008;Gidekel Friedlander et al 2009;Kopp et al 2012;Puri et al 2015). However, comprehensive studies that target diverse genomic alterations to a greater array of defined cell types are simply not feasible using current transgene-based systems.…”

Acinar‐to‐ductal metaplasia accompanies c‐myc‐induced exocrine pancreatic cancer progression in transgenic rodents

“…These observations supported suggestions that acinar-to-ductal metaplasia could develop within acinar cell carcinomas. 5 Subsequent to that study, we 6 and other workers 7,8 demonstrated that acinar cell targeted expression of mutant Kras caused acinar-to-ductal metaplasia in non-neoplastic pancreas, leading to preneoplastic pancreatic intraductal neoplastia. Cells lining these structures display morphological features of ductal epithelium.…”

Pancreatic carcinoma development: new etiological and pathogenetic evidence

“…Nevertheless, recent studies report that at least a part of pancreatic carcinoma may originate from acinar or centro-acinar cells or develop in specialized pancreatic compartments, represented by the gland-like mucinous outpouches of major ducts. 55,56 In particular, available experimental evidence seems to suggest that, in a context of persistent inflammation in pancreatic tissue, a process characterized by acinar-to-ductal mucinous metaplasia may occur. Furthermore, in this organ, human acinar cells adjacent to areas of cancer present ductal markers.…”