eIF4G2-dependent translation restrains pancreatic cancer progression

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 metastatic spread. Ribosome profiling revealed that eIF4G2 loss did not increase bulk protein synthesis but instead suppressed 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.