[en] During cancer progression, neutrophils undergo transcriptional reprogramming and acquire a Tumor-Associated Neutrophil (TAN) phenotype. TANs exhibit functional plasticity, exerting either pro-tumoral activities by promoting tumor growth and metastasis, or anti-tumoral effects by inhibiting epithelial cell proliferation and modulating angiogenesis. In metastatic breast cancer, early neutrophilia is linked to poor outcomes. Neutrophils contribute to metastasis by facilitating the formation of a pre-metastatic niche, particularly in the lungs.
Using low-throughput proteomics, we showed that neutrophils undergo metabolic reprogramming when infiltrating the primary tumor. Normally glycolysis-dependent and using glycogen stores under low glucose, tumor-infiltrating neutrophils shift to mitochondrial metabolism. Neutrophils from cancer patients show increased oxidative phosphorylation (OXPHOS) and a more immature phenotype. This shift is paired with increased expression of tRNA-modifying (U34-TM) enzymes, which affect the wobble position in tRNAs. We found that U34-TM enzymes (Elp3, Alkbh8, Ctu1/2) are upregulated in neutrophils from breast tumor-bearing mice compared to tumor-free controls.
We hypothesized that U34-TM supports metabolic reprogramming via translational control during cancer progression. To test this, we created a neutrophil-specific U34-TM loss-of-function model by crossing Elp3lox/lox mice with the Mrp8-Cre strain. Elp3 deletion reduced neutrophil numbers in the lungs and spleens of tumor-bearing mice and significantly lowered metastatic burden in PyMT mice. Unexpectedly, it also led to fewer and smaller primary tumors. Additionally, Elp3 loss changed mitochondrial morphology and altered the metabolic state of TANs.
These findings reveal a key role for U34-TM in regulating neutrophil function in breast cancer. Our ongoing work focuses on understanding the immune regulatory networks behind the anti-tumoral response and the translational changes in neutrophils within the tumor microenvironment.
