Axl promotes metastasis of pancreatic cancer by regulating an EMT programm


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Lankhanh Trinh1,Dieter Saur1
1Rechts der Isar Hospital

Abstract

Background

Pancreatic cancer (PDAC) is the fourth leading cause of cancer death in the US. The most common pancreatic cancer type, pancreatic ductal adenocarcinoma (PDAC), has a 5-year survival of less than 5% despite maximal treatment. Metastases in liver, lung or peritoneal cavity can aggravate the prognosis even in the early stages of PDAC. Therefore, we need to study the mechanism behind aggressive growth and metastasis of PDAC. The Axl gene encoding for a receptor tyrosine kinase is involved in proliferation, epithelial-mesenchymal transition and plays an important role in the development of metastases.

Method

We used KrasG12D and PIK3CAH1047R mutant mice and activated the oncogene with the pancreas specific Ptf1a-Cre line. We compared the effect of homozygote knock out (KO) of Axl and heterozygote KO with the wild-type control group. We counted preneoplastic PanIN lesions, determined PDAC histology and the occurrence of metastases. Furthermore, we analyzed important signaling pathways, such as Erk-Mek-Map and PI3K/Akt in wild-type and Axl KO mice.

Results

No significant differences in the relative pancreas weight and in the number of precursor lesions were found in 3 months old mice of the KrasG12D model. In contrast, we observed an increased amount of PanIN lesions in the PIK3CAH1047R Axl KO model. In 30% (8 of 24 mice) of the KrasG12D control group, liver, lung or lymph node metastases occur. In the Axl-KO group of the KrasG12D model, the metastasis rate decreased to 10% (1 of 10 mice), which correlated with a decreased mRNA expression of important EMT marker genes, such as vimentin, and an increased expression of epithelial markers, such as E-cadherin.

Conclusion

Axl is an important mediator of EMT and metastasis of pancreatic cancer.