Loss of ATM increases pancreatic cancer formation via induction of EMT
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer deaths in the developed world, with a 5 year survival rate as low as 5%. In recent years, genetically engineered animal models of pancreatic cancer, which recapitulate the human disease, have provided useful means of studying both the morphological and molecular features associated with PDAC. The most commonly studied model to date has been the expression of active Kras under the control of an endogenous, pancreas specific promoter, which leads to a spectrum of changes in the pancreas recapitulating development of human PDAC. Interestingly, PDAC develops much more rapidly when further oncogenes such as SMAD4 or p53 are deleted. In the current study, we address the role of Ataxia Telangiectasia Mutated (ATM) gene in PDAC and describe a loss of ATM protein with advanced UICC stage in primary human tumor specimens. We also found that mutations in the ATM gene are more abundant in large collectives of human pancreatic cancer. Subsequently, we show that loss of ATM enhanced the metastatic potential of the Kras mouse model and decreased survival of mice to 36 and 38 weeks for homozygous and heterozygous ATM deletion, respectively. These mice developed a greater number of pre-malignant pancreatic intraepithelial neoplasias (mPanINs) with a significant increase in proliferation and α-smooth muscle actin positive cells, indicative of activated pancreatic stellate cells (PSCs). This was followed by an increase in large, dysplastic papillary lesions and a significant amount of surrounding fibrosis compared to controls. Our results furthermore establish that the loss of ATM in this mouse model promoted EMT via an increased response to BMP4-signalling. Moreover, early EMT upon ATM loss was associated with increased invasive properties. Taken together, our data suggests that there may be an intimate link between ATM activity and pancreatic cancer formation, one of the major signalling pathways altered in PDAC and targeting this axis may provide therapeutic potential in the future.