Pten Is a Major Tumor Suppressor in Pancreatic Ductal Adenocarcinoma and Regulates an NF-κB-Cytokine Network

Pancreatic ductal adenocarcinoma (PDAC) initiation is driven by oncogenic KRAS mutation and disease progression is associated with frequent loss of tumor suppressors. In this study, human PDAC genome analyses revealed frequent deletion of the PTEN gene as well as loss of expression in primary tumor specimens. A potential role for PTEN as a haploinsufficient tumor suppressor is further supported by mouse genetic studies. The mouse PDAC driven by oncogenic Kras mutation and Pten deficiency also sustains spontaneous extinction of Ink4a expression and shows pro-metastatic capacity. Unbiased transcriptomic analyses established that combined oncogenic Kras and Pten loss promotes marked NF-κB activation and its cytokine network with accompanying robust stromal activation and immune cell infiltration with known tumor promoting properties. Thus, PTEN/PI3K pathway alteration is a common event in PDAC development and functions in part to strongly activate the NF-κB network which may serve to shape the PDAC tumor microenvironment.