Chio, C. I. I. | bioRxiv Science

bioRxiv2026

eIF4G2-dependent translation restrains pancreatic cancer progression

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.

cancer biology↗

bioRxiv2025

TMPO promotes cellular dissemination and metastasis in circulating tumor cells

Metastasis--the process by which cancer cells spread beyond the primary tumor to distant organs--accounts for the vast majority of cancer-related deaths. To elucidate mechanisms underlying dissemination and metastasis in prostate cancer, we have investigated circulating tumor cells (CTCs) obtained from genetically engineered mouse models (GEMMs). The phenotypic and molecular properties of the CTCs, and organoids derived from these CTCs, closely model the tumor and metastatic phenotypes of their parental GEMMs. Moreover, organoids derived from individual CTCs exhibit molecular and morphological heterogeneity that is associated with distinct metabolic states as well as differences in human prostate cancer outcome. Using computational systems analyses, we have identified TMPO, encoding the nuclear membrane protein lamina-associated polypeptide 2 (Lap2), as a key driver of this heterogeneity. TMPO activity is upregulated in advanced human prostate tumors, metastases, and CTCs, and is associated with adverse clinical outcome. Our findings indicate that TMPO promotes dissemination and metastasis in vivo by enhancing survival in conditions of metabolic stress, and reveal a novel mechanistic link between CTC heterogeneity, stress adaptation, and metastatic potential.

cell biology↗