Abstract A063: UNC5B orchestrates the metastatic traits of pancreatic ductal adenocarcinoma through EMT, invasion, and survival signaling

Abstract Metastasis is a hallmark of Pancreatic Ductal Adenocarcinoma (PDAC) and is driven by a complex cascade of coordinated processes, including epithelial-to-mesenchymal transition (EMT), enhanced invasion and migration, survival, and the acquisition of stem-like properties. Our studies identify UNC5B as a critical driver of metastasis in PDAC. Using a genetically engineered mouse model (KPCU), we demonstrate that deletion of UNC5B in primary tumor cells completely abolishes metastatic dissemination, whereas over 85% of mice with intact UNC5B expression in primary tumor cells develop metastases. Mechanistically, UNC5B receptor regulates several key factors of metastasis properties through distinct pathways. UNC5B promotes EMT through regulation of the ZEB1 transcriptional program and drives cellular invasion via SRC-mediated signaling. UNC5B overexpression resulted in increased ZEB1 expression, while UNC5B knockdown led to a significant reduction in ZEB1 levels, with no observable changes in other EMT-inducing transcription factors. Notably, knocking down ZEB1 in these cells reverted the mesenchymal phenotype to epithelial-like state, highlighting the central role of ZEB1 in the UNC5B–mediated EMT program. Indeed, UNC5B enhanced basal-like phenotype of Human PDAC cells by which the PAMG score decreased and by depletion of UNC5B PAMG score elevated in the same cell line, introducing a new receptor that mediates EMT program in cancer field. We further identified a novel link between UNC5B and SRC signaling, demonstrating that UNC5B overexpression elevates total SRC levels while concurrently decreasing SRC Tyr530 phosphorylation, suggesting that UNC5B may modulate SRC activity to facilitate invasive behavior. As UNC5B over-expression promoted the invasion of Human PDAC through SRC-mediated signaling in which knocking down the SRC mitigated this phenomenon. Interestingly, UNC5B appears to enhance the survival of disseminated or detached tumor cells by preventing anoikis. We speculate that UNC5B may support cell survival through modulation of the AKT pathway, as UNC5B deletion was associated with elevated phosphorylation of AKT at Ser473—a possible compensatory response to cellular stress or crisis triggered by UNC5B loss. In summary, Several Metastasis properties of PDAC is under the umbrella of UNC5B function. Citation Format: Muhammad Sadeqi Nezhad, Chris R. Harris, Darren R. Carpizo. UNC5B orchestrates the metastatic traits of pancreatic ductal adenocarcinoma through EMT, invasion, and survival signaling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A063.