Loss of ATM accelerates KrasG12D – induced pancreatic cancer formation

Abstract

Onset and progression of pancreatic ductal adenocarcinoma (PDAC) is associated with the accumulation of certain oncogenic mutations and more recently, genome-wide exome sequencing studies have identified ATM mutations in independent PDAC cohorts. However, the role of ATM is in PDAC initiation and progression is unclear. Here we report that conditional deletion of ATM in a mouse model of PDAC enhanced pancreatic cancer formation via induction of ductal reprogramming. Notably, there was an increase in tumour formation due to ATM haploinsufficiency. This resulted in a significantly shortened survival of AKC-mice compared to controls (KC-mice). These AKC-mice developed a greater number of proliferative acinar-to-ductal metaplastic (ADM) lesions and pancreatic intraepithelial neoplasias (PanIN) and these were associated with a pronounced fibrotic reaction. The precursor lesions were broadly associated with on-going epithelial-to-mesenchymal transition (EMT) and a gain of tumor initiating cells, which were more numerous in AKC-mice. Furthermore, we noticed an elevated TGFß-signaling, a known EMT regulator, in ATM-depleted pancreatic tissue. Global gene expression analysis indicated that PDAC tumors derived from ATM-deficient mice correlate well with human mesenchymally differentiated PDAC. Finally, we show that ATM mutations are abundant in large cohorts of human PDAC and low ATM expression correlates with shortened overall survival in humans. Our results indicate that ATM is a tumor suppressor molecule and low expression of ATM serves as a prognostic marker in PDAC. Taken together, our data suggests an intimate link between ATM expression and pancreatic cancer formation in mice and men.