eIF4G2-dependent translation restrains pancreatic cancer progression

Area of Science:

• Molecular Biology
• Cancer Research
• Translational Control

Background:

• Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer characterized by cellular plasticity, therapeutic resistance, and metastasis.
• The role of translational control in PDA plasticity and progression is not well understood.

Purpose of the Study:

• To investigate the contribution of translational control to PDA plasticity.
• To identify key regulators of translational control in PDA progression.

Main Methods:

• *in vivo* CRISPR/Cas9 screening
• Ribosome profiling
• Functional studies
• Computational inference from human PDA datasets

Main Results:

• The non-canonical initiation factor eIF4G2 (DAP5/NAT1) acts as a translational checkpoint restraining PDA progression.
• Loss of eIF4G2 accelerates tumor growth, induces poorly differentiated histology, and promotes metastasis.
• eIF4G2 loss impairs translation of a selective set of proteins, including tumor suppressors PTEN and CREBBP, impacting cell differentiation and migration.
• Reduced eIF4G2 activity in human PDA metastases correlates with basal-like features and predicts poorer survival.

Conclusions:

• eIF4G2 maintains epithelial identity and restrains metastatic potential in PDA.
• Selective translation regulated by eIF4G2 is a key determinant of PDA subtype and clinical outcome.
• Targeting eIF4G2-mediated translational control may offer therapeutic strategies for PDA.