Targeting of surface alpha-enolase inhibits the invasiveness of pancreatic cancer cells

Pancreatic Ductal Adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by rapid progression, invasiveness and resistance to treatment. We have previously demonstrated that most PDAC patients have circulating antibodies against the glycolytic enzyme alpha-enolase (ENO1), which correlates with a better response to therapy and survival. ENO1 is not only a cytoplasmic enzyme but is also expressed on the cell surface where it acts as a plasminogen receptor. By promoting plasminogen activation into plasmin, a serine-protease involved in extracellular matrix degradation, ENO1 plays a crucial role in cell invasion and metastasis. The aim of this study was to investigate the role of ENO1 in PDAC cell invasion. We observed that ENO1 was expressed on the cell surface of most PDAC cell lines. Moreover, two different mouse anti-human ENO1 monoclonal antibodies (mAbs; 72/1 and E10A) inhibited plasminogen-dependent invasion of human PDAC cells and metastatic spreading in immunosuppressed mice. Notably, a single administration of Adeno-Associated Virus (AAV)-expressing cDNA coding for 72/1 anti-ENO1 mAb reduced the number of lung metastases in immunosuppressed mice injected with PDAC cells. Overall, these data indicate that ENO1 is involved in PDAC cell invasion, and that administration of an anti-ENO1 mAb can be exploited as a novel therapeutic option to increase the survival of metastatic PDAC patients.