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

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease despite tremendous scientific efforts. Numerous trials have failed to improve the outcome on this deadliest of all major cancers. Potential causes include a still insufficient understanding of key features of this cancer and imperfect preclinical models for identification of active agents and mechanisms of therapeutic responses and resistance. Modern genetically engineered mouse models of PDAC faithfully recapitulate the genetic and biological evolution of human PDAC, thereby providing a potentially powerful tool for addressing tumour biological issues as well as strategies for early detection and assessment of responses to therapeutic interventions. Here, the authors will discuss opportunities and challenges in the application of genetically engineered mouse models for translational approaches in pancreatic cancer and provide a non-exhaustive list of examples with already existing or future clinical relevance.

Modeling Therapy Response and Spatial Tissue Distribution of Erlotinib in Pancreatic Cancer

“…Modeling these hallmark characteristics of PDAC in vivo using xenograft models has been largely disappointing, while genetically engineered mouse models (GEMM) based on pancreas-specific activation of oncogenic mutant Kras faithfully recapitulate the morphologic and molecular characteristics of human PDAC enabling sophisticated preclinical approaches (reviewed in ref. 2).…”

State of the art and future directions of pancreatic ductal adenocarcinoma therapy

“…p16/CDKN2A gene alteration is also an early genetic event found in PanIN-1 and PanIN-2, while the higher grade PanIN-3 lesions and invasive adenocarcinoma often harbor additional mutations in TP53, BRCA2, and TGFβ/SMAD4 pathway genes (Hruban et al, 2000;Kanda et al, 2012). Genetically engineered PDAC mouse models consistently recapitulate this genetic and biological evolution (Mazur & Siveke, 2012;Morris et al, 2010). In addition, whole-exome sequencing studies revealed that mutations in DNA damage response genes are prevalent in both PanIN and PDAC and that genes encoding proteins involved in gap junctions, actin cytoskeleton, mitogen-activated protein kinase (MAPK) signaling pathway, axon guidance, and cell-cycle regulation are among the earliest targets of mutagenesis in PanIN that progress to PDAC (Murphy et al, 2013).…”

The role of insulin and IGF system in pancreatic cancer

“…through the process of acinar to ductal metaplasia followed by malignant transformation (Hezel et al 2006, Mazur & Siveke 2012. Exocrine cells are in the vicinity of the islets of Langerhans and are thus directly exposed to high insulin concentrations.…”

“…Though of low incidence, late detection and lack of effective chemotherapies make this cancer one of the deadliest, with a 5-year overall survival rate lower than 5% (Li et al 2004, Jemal et al 2008. In the last decade, substantial research efforts in investigating pancreatic carcinogenesis have broadened our knowledge and many molecular mechanisms essential for PDAC carcinogenesis and its maintenance have been described (Hingorani et al 2005, Siveke & Schmid 2005, Izeradjene et al 2007, Mazur & Siveke 2012. Still, efficient therapies are missing and targeted approaches have been largely disappointing.…”