Genetically engineered mouse models of pancreatic adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of human cancer for which there are no effective therapies. Deep sequencing of PDAC tumors has revealed the presence of a high number of mutations (>50) that affect at least a dozen key signaling pathways. This scenario highlights the urgent need to develop experimental models that faithfully reproduce the natural history of these human tumors in order to understand their biology and to design therapeutic approaches that might effectively interfere with their multiple mutated pathways. Over the last decade, several models, primarily based on the genetic activation of resident KRas oncogenes knocked-in within the endogenous KRas locus have been generated. These models faithfully reproduce the histological lesions that characterize human pancreatic tumors. Decoration of these models with additional mutations, primarily involving tumor suppressor loci known to be also mutated in human PDAC tumors, results in accelerated tumor progression and in the induction of invasive and metastatic malignancies. Mouse PDACs also display a desmoplastic stroma and inflammatory responses that closely resemble those observed in human patients. Interestingly, adult mice appear to be resistant to PDAC development unless the animals undergo pancreatic damage, mainly in the form of acute, chronic or even temporary pancreatitis. In this review, we describe the most representative models available to date and how their detailed characterization is allowing us to understand their cellular origin as well as the events involved in tumor progression. Moreover, their molecular dissection is starting to unveil novel therapeutic strategies that could be translated to the clinic in the very near future.

Figure 1

Genetically engineered mouse models of cancer faithfully reproduce the histological changes characteristic of human PDAC tumors. (A) Schematic diagram of the preneoplastic lesions that precede the development of PDAC (modified from the Hruban et al., 2005). (B) Representative PanIN lesions and PDAC observed in the Elas‐tTA; Tet‐O‐Cre; KRasLSLG12Vgeo strain. Similar lesions appear in the Pdx1‐Cre; LSL‐KRasG12D (KC) model and in the Ptf1a/P48‐Cre; LSL‐KRasG12D. (C) Schematic diagram of the timing at which the resident knocked in KRas oncogenes are expressed during embryonic development in the various models. (D) Schematic diagram of the timing at which the resident knocked‐in KRas oncogenes are expressed in adult mice in two independent models of PDAC. In the Elas‐tTA; Tet‐O‐Cre; KRasLSLG12Vgeo strain, the pregnant mothers and their offspring are exposed to doxycycline in the drinking water to prevent expression of the resident KRasG12V oncogene until the animals are at least 8 weeks old. These mice do not develop any lesions unless they undergo pancreatitis. In the Elas‐CreERT2; LSL‐KRasG12D model expression of the endogenous KRasG12D oncogene is mediated by exposure to tamoxifen, an estrogen analog that selectively activates the inducible CreERT2 recombinase.