Invasive pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of any major malignancy and is the 4th leading cause of cancer-related deaths in the USA. Using a widely-used mouse model of oncogenic Kras-driven pancreatic cancer (KC mice) we discovered that Prox1-haploinsufficiency enhances neoplastic pancreas transformation downstream of Kras, and sensitizes to chemically induced acute pancreatitis (Drosos et al., Neoplasia, 2016). Follow-up studies in the lab are investigating how Prox1 protects pancreatic exocrine cells from transformation or sustained inflammation.
Most PDAC patients present with metastatic disease at the time of diagnosis and few show a durable response to chemotherapy or radiotherapy. About 5% of patients with hereditary pancreatic cancer have germline mutations in the gene ATM, and a fraction of human pancreatic tumors classified as ‘genetically unstable’ also present deleterious ATM mutations. ATM encodes a kinase that helps to preserve the integrity of the genome because it activates responses downstream of DNA damage. In line with the former observations, we recently demonstrated that the functional inactivation of Atm increases metastatic pancreatic cancer incidence in KC mice. Additionally, we also found that murine pancreatic tumor cells that lack Atm activity have a high degree of genomic instability and display high sensitivity to irradiation exposure (Drosos et al., Sci. Rep. 2017). Ongoing efforts in the lab focus on establishing how ATM function poses a barrier to pancreas tumor formation and understanding why ATM deficient pancreatic tumors are highly metastatic.