Year: 2026
Type: article
Abstract: The lethality of pancreatic ductal adenocarcinoma (PDAC) is driven, in part, by cellular plasticity that facilitates dedifferentiation and dissemination. Although transcriptional programs underlying these processes are well characterized, the contribution of translational control to PDAC cell-state regulation in vivo needs to be further understood to develop strategies to restrain malignant plasticity. Using a genome-wide CRISPR/Cas9 screen in immunocompetent hosts, we identified the noncanonical initiation factor eIF4G2 (DAP5/NAT1) as a translational checkpoint that restrains PDAC progression. Loss of eIF4G2 accelerated tumor growth, promoted poorly differentiated, basal-like histology, and triggered widespread metastasis. Ribosome profiling revealed that eIF4G2 supports the translation of a discrete cohort of mRNAs with long, guanine-cytosine (GC)-rich, structured 5' untranslated regions, including tumor suppressors such as Pten and transcriptional regulators such as Crebbp. Accordingly, loss of eIF4G2 was accompanied by secondary transcriptional enrichment of migration and wound-healing programs and induction of basal-like markers. In human PDAC, eIF4G2 expression was reduced in poorly differentiated lesions, and functional eIF4G2 perturbation in patient-derived PDAC cells increased clonogenic growth, whereas enforced eIF4G2 expression suppressed colony formation. Computational inference from human PDAC datasets revealed that reduced eIF4G2 activity correlated with increased metastasis, enhanced basal-like features, and poorer patient survival. Together, these findings establish noncanonical translation initiation as a determinant of PDAC cell-state control and identify eIF4G2 as a barrier to malignant plasticity and metastatic dissemination. SIGNIFICANCE: The translational checkpoint regulator eIF4G2 preserves epithelial identity and suppresses metastasis in pancreatic cancer, revealing selective translation as a determinant of subtype, prognosis, and therapeutic stratification.
Source: Cancer Research
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Irma T. Hirschl Trust, Pershing Square Sohn Cancer Research Alliance, Mark Foundation For Cancer Research, National Institutes of Health, Irving Medical Center, Columbia University, Mega-projects of Science Research for the 10th Five-Year Plan, National Cancer Institute, Basic Research Laboratory, All of Us Research Program
Awards: NRF2-dependent redox signaling in pancreatic cancer, G3462389792, G3668548152, Methods to Rapidly Explore Combinatorial Diversity and their Application to CRISPR-Cas9 Systems, G7190607648, G9000160336, Studying the role of eIF4A in Pancreatic Cancer, Buffett Cancer Center Support Grant, Characterizing the role of MSRA in pancreatic tumorigenesis, Cancer Center Support Grant
OpenAlex ID: W7162566440
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