UNC5B regulates epithelial-to-mesenchymal transition through a SRC-ZEB1 signaling axis to facilitate pancreatic cancer metastasis

Metastatic dissemination is the principal cause of death in pancreatic ductal adenocarcinoma (PDAC), yet the molecular determinants that enable this process remain poorly understood. Here, we identify the axon guidance receptor UNC5B as a central regulator of PDAC metastasis. Using both genetically engineered KPCU and orthotopic mouse models, we demonstrate that loss of UNC5B completely abolishes metastatic spread, reduces tumor proliferative capacity, increases intratumoral necrosis, confining tumors to the pancreas with no invasion into adjacent tissues or lymph nodes and preserving epithelial morphology. Mechanistically, UNC5B drives epithelial-to-mesenchymal transition (EMT) and invasion through activation of the SRC-ZEB1 axis. Notably, UNC5B specifically engages ZEB1 to drive EMT, without altering other canonical EMT transcription factors such as SNAIL or TWIST1. Pharmacological degradation of exogenous UNC5B using a targeted protein degrader (degron) modulated EMT and invasive behavior in PDAC cells. Acute depletion of UNC5B resulted in a marked reduction in EMT scores, accompanied by decreased ZEB1 and SRC levels. Together, these findings identify UNC5B as a central molecular hub governing metastatic competence in PDAC by promoting EMT and invasion.