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Significance Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, attributed in part to lineage infidelity downstream of deregulated lineage-specifying transcription factors (TFs). Here we define the biological effects of a poorly understood TF ZBED2 in the most aggressive subtype of PDA, defined by the expression of squamous lineage markers. Our study reveals two molecular functions of ZBED2 in PDA cells: An inhibitor of interferon response genes and a modifier of epithelial lineage programs. Both functions can be explained by the ability of ZBED2 to antagonize the functional output of interferon regulatory factor 1 (IRF1). Our study reinforces the concept of aberrant lineage identity in cancer and highlights an unexpected connection between interferon response pathways and squamous-subtype PDA.

ZBED2 is an antagonist of interferon regulatory factor 1 and modifies cell identity in pancreatic cancer