Data from: eIF4E S209 phosphorylation licenses myc- and stress-driven oncogenesis

Mutational activation of Wnt/Myc and RAS signaling promotes colorectal
cancer (CRC) development and deregulates translation. Phosphorylation of
the cap binding protein eIF4E (Serine 209) is commonly elevated in cancer
such as CRC yet dispensable for normal development. To better understand
an oncogenic role of eIF4ES209, we generated eIF4E (S209A/+) heterozygous
knockin (4EKI) HCT 116 human colorectal cancer (CRC) cells. 4EKI had
little or no effect on total eIF4E levels, cap binding or global
translation, while markedly reduced HCT 116 cell growth in spheroids and
mice. 4EKI strongly inhibited Myc and ATF4 translation, the integrated
Stress Response (ISR)-dependent glutamine metabolic signature, AKT
activation and proliferation in vivo. p-eIF4E was found to be
highly elevated in CRC precursor lesions in mouse and human.
4EKI inhibited polyposis in APC+/min mice by suppressing Myc
protein and AKT activation. Furthermore, mutant KRAS cooperated with
p-eIF4E and Myc to promote ISR-dependent glutamine addition in various CRC
cell lines, which was characterized by increased cell death,
transcriptomic heterogeneity and immune suppression upon deprivation.
These findings demonstrate a critical role of eIF4ES209-dependent
translation in Myc and stress-driven oncogenesis and as a potential
therapeutic vulnerability.