The role of insulin receptor and insulin-like growth factor I receptor in pancreatic ductal adenocarcinoma
Aims: PDAC ist the fourth leading cause of malignancy related deaths in humans due mainly to the lack of effective therapies. Insulin and Insulin-like growth factors and their receptors (IR and IGF1R) have been acknowledged as important players in a variety of cancers. The aim of this study is to investigate the role of IR and IGF1R in PDAC initiation and progression.
Methods: Multiple genetically engineered mouse models (GEMM) targeting oncogenic and tumor suppressive genes combined with pancreas-specific deletion of IGF1R and IR were generated and characterized. Various molecular and metabolic analyses were used to examine the influence of these two receptors for PDAC formation, progression and essential downstream pathways.
Results: GEMM developing endogenous PDAC with either IGF1R or IR deletion showed a greatly reduced PanIN formation and surprisingly no progression to cancer. Notable, the lack of only one of these receptors was sufficient to effectively block tumor development. Additional immunoprecipitation results indicated an essential role of IGF1R/IR hybridreceptors for PDAC development. Proliferation of PanINs was reduced in KrasG12D;Igf1Rko and KrasG12D;IRko mice compared to KrasG12 D controls. Analyzing different downstream signaling pathways we found pAKT to be significantly regulated, indicating strong regulation of PI3K signaling by IGF1R and IR. Selective genetic targeting of either PI3K or MEK using respective novel GEMM supported IR/IGF1R targeting of the PI3K signaling pathway.
Conclusion: A functional IR/IGF1R signaling network involving IR/IGF1R hynrid receptors and PI3K downstream signaling is essential for the development and progression of PDAC.