Deploying Mouse Models of Pancreatic Cancer for Chemoprevention Studies

Abstract

With the advent of mouse models that recapitulate the cellular and molecular pathology of pancreatic neoplasia and cancer, it is now feasible to recruit and deploy these models for the evaluation of various chemopreventive and/or anticancer regimens. The highly lethal nature of pancreatic ductal adenocarcinoma (PDAC) makes multiple areas of research a priority including assessment of compounds that prevent or suppress the development of early lesions that can transform into PDAC. Currently, there are over a dozen models available, which range from homogeneous preneoplastic lesions with remarkable similarity to human pancreatic intraepithelial neoplasms (PanINs) to models with a more heterogeneous population of lesions including cystic papillary and mucinous lesions. The molecular features of these models may also vary in a manner comparable to the differences observed in lesion morphology, and so navigating the route of model selection is not trivial. Yet, arming the community of cancer investigators with a repertoire of models and the guidance to select relevant models that fit their research themes promises to produce findings that will have clinical relevance.

Genetically engineered mouse models of pancreatic cancer: unravelling tumour biology and progressing translational oncology

“…Notably, inhibition of EGFR and Notch signalling led to an impressive reduction in PDAC development, suggesting that these cell fate regulating pathways may be a valuable approach for targeting preneoplastic lesions or early PDAC. Further chemopreventive approaches, which are summarised in two recent overviews, have been reported 66 67. Notably, the success of GEMM for such chemopreventive strategies in terms of clinical relevance will likely depend on the applicability of results and the predictive value for clinically useful interventions and not so much on an exact recapitulation of all features of the respective human disease.…”

Experimental Animal Models of Pancreatic Carcinogenesis for Prevention Studies and Their Relevance to Human Disease

“…One focuses on suppression of PanIN development in LsL- Kras G12D ; Pdx1-Cre mice or LsL- Kras G12D ; p48-Cre mice. In this system, incidences of pancreatic cancer are low (∼20% at one year) [155], and therefore, it is difficult to obtain statistically significant results for cancer development. The PanIN lesions in GEM mice have similar phenotypes to humans, such as COX-2 [124] and LOX-5 [126] expression, but the pathological process of development of early lesions is quite different from human cases.…”

Optimizing mouse models for precision cancer prevention

“…, 14, 16, 18 ). Nevertheless, considering the expansive body of chemoprevention studies in mice, the corresponding clinical impact for human cancer prevention has been relatively modest.…”

“…Pancreatic cancer is well represented by informative GEM models 102 , which have been employed for various aspects of cancer prevention 16 , including the identification of potential biomarkers for early detection. Notably, a recent study integrated human epidemiological data with experimental studies in mouse models to reveal and mechanistically explain the finding that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with increased risk for pancreatic cancer years prior to disease presentation 103 .…”