Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with which many patients are diagnosed post-metastatic dissemination, making elucidation of molecular mechanisms underlying PDAC metastasis imperative. While increased MUC16 expression during tumor progression implicates MUC16 as a contributor to the metastatic cascade, how MUC16 might augment metastasis has not been solved. In their study on page 1208, Marimuthu and colleagues utilized human PDAC metastatic tissues, cell lines, and organoids to interrogate the role of MUC16 in PDAC liver metastasis. Depicted on the cover is a merged immunofluorescent image of a PDAC patient-derived organoid in which cytokeratin 19-expressing PDAC cells fluoresce red, MUC16 fluoresces green, and DAPI-stained nuclei fluoresce blue. The authors found that MUC16 is expressed in PDAC primary tumors and metastatic lesions but not in normal pancreatic epithelial cells. Mechanistically, the authors demonstrated that MUC16 increases neuropilin-2 (NRP2) abundance by activating signal transducers and activators of transcription 1 (STAT1)/Janus kinase 2 (JAK2) signaling, augmenting PDAC liver metastasis. This article is also Highlighted on page 1181.