eIF4E S209 phosphorylation licenses myc- and stress-driven oncogenesis

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Phosphorylation of eukaryotic initiation factor 4E (eIF4E) at serine 209 (S209) is implicated in oncogenesis.
• Understanding the precise role of eIF4E S209 in colorectal cancer (CRC) translation and tumor development is critical.

Purpose of the Study:

• To investigate the functional significance of eIF4E S209 phosphorylation in human colorectal cancer (CRC) cell growth and oncogenic translation.
• To determine the impact of inhibiting eIF4E S209 phosphorylation on key cancer pathways and tumor progression.

Main Methods:

• Generation of EIF4E heterozygous knockin (4EKI) HCT 116 cells to mimic reduced eIF4E S209 phosphorylation.
• Assessment of cell growth in 2D spheroids, 3D organoids, and in vivo mouse models (including Apc mice).
• Analysis of protein translation (Myc, ATF4), integrated stress response (ISR), AKT activation, and metabolic signatures.

Main Results:

• 4EKI cells exhibited significantly reduced HCT 116 cell growth in spheroids, organoids, and mouse models.
• eIF4E S209 inhibition markedly suppressed Myc and ATF4 translation, AKT activation, and proliferation in vivo.
• Elevated p-eIF4E levels in CRC precursor lesions correlated with mutant KRAS, promoting Myc and ISR-dependent glutamine addiction.
• Deprivation in p-eIF4E-driven CRC cells led to increased cell death, transcriptomic heterogeneity, and immune suppression.

Conclusions:

• eIF4E S209-dependent translation plays a critical role in Myc and stress-driven colorectal cancer (CRC) oncogenesis.
• Inhibition of eIF4E S209 phosphorylation represents a potential therapeutic vulnerability for CRC treatment.
• Targeting eIF4E S209 may impact tumor growth, metabolic reprogramming, and the tumor microenvironment in CRC.