Ying and colleagues identify a novel function of Pten as a haploinsufficient tumor suppressor in human pancreatic cancer development. Genomic, genetic, and biochemical data reveal that Pten loss and Kras mutation cooperate to accelerate pancreatic cancer development by altering PI3K regulation to enhance NF-κB activation and upregulate downstream cytokine genes; this provides a protumorigenic and metastatic microenvironment.