Loss of tumor suppressor WWOX enhances RAS activity in pancreatic cancer

Pancreatic cancer is one of the most lethal cancers, due to late diagnoses and chemotherapy resistance. The tumor suppressor WWOX, spanning one of the most active common fragile sites in the human genome (FRA16D), is commonly altered in pancreatic cancer. However, the direct contribution of WWOX loss to pancreatic cancer development and progression is largely unknown. Here, we report that combined conditional deletion of Wwox and activation of KRasG12D in Ptf1a-CreER -expressing mice resulted in accelerated formation of precursor lesions and pancreatic carcinoma. In addition, these mice displayed enhanced MAPK and IL6/Jak/Stat3 signalling, combined with higher rates of macrophage infiltration and inflammation signature at sites of acinar to ductal metaplasia (ADM). Moreover, accumulated DNA double strand breaks were observed at ADM lesions. Finally, overexpression of WWOX in patient-derived xenografts led to reduction in KRAS MAPK activity and IL6/Jak/Stat3 signalling so diminishing their aggressiveness and in vivo tumor growth. Our data underscore the important role of WWOX in regulating RAS activity in pancreatic carcinogenesis.