Powers, J.; Lai, W.; Ahmadi, P.; KOBAYASHI, H.; Curiel Garcia, A.; Valenzuela, E.; Jovanovic, M.; Chavez, A.; Chio, C. I. I.

Pancreatic ductal adenocarcinoma (PDA) is among the most lethal cancers, driven by cellular plasticity that fuels therapeutic resistance and early dissemination. The contribution of translational control to this plasticity remains poorly understood. Through an in vivo CRISPR/Cas9 screen, we identify the non-canonical initiation factor eIF4G2 (DAP5/NAT1) as a translational checkpoint restraining PDA progression. Loss of eIF4G2 accelerated tumor growth, induced poorly differentiated, basal-like histology, and triggered widespread metastasis. Ribosome profiling revealed that eIF4G2 loss does not alter bulk protein synthesis but instead impairs translation of a selective regulon, including tumor suppressors such as PTEN and CREBBP. Functional studies confirmed that PTEN loss was sufficient to drive dedifferentiation but insufficient to promote metastasis, implicating the broader eIF4G2-dependent program, including translational control of transcriptional regulators like CREBBP, in limiting dissemination. Consistently, eIF4G2-deficient tumors exhibited transcriptomic enrichment of programs related to migration and wound healing. Computational inference from human PDA datasets revealed reduced eIF4G2 activity in metastases, aligning with basal-like features and predicting poorer survival. These results support a model in which eIF4G2 maintains epithelial identity and restrains metastatic potential, highlighting selective translation as a determinant of PDA subtype and clinical outcome.