[en] During cancer progression, neutrophils undergo transcriptional reprogramming that leads to the acquisition of 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, neutrophilia is observed at early stages and is associated with poor clinical outcomes. Neutrophils contribute to metastasis by facilitating the formation of a pre-metastatic niche, particularly in the lungs. Using low-throughput proteomic approaches, we demonstrated that neutrophils undergo a metabolic reprogramming. Although neutrophils are classically reliant on glycolysis and maintain glycogen stores to engage in glycogenolysis under low-glucose conditions, they switch to mitochondrial metabolism upon tumor infiltration. Notably, neutrophils from cancer patients display an enhanced oxidative phosphorylation (OXPHOS) signature and exhibit a more immature phenotype.
This metabolic transition is accompanied by the upregulation of tRNA-modifying enzymes that specifically affect the wobble position. Indeed, our laboratory recently revealed the crucial role of wobble uridine tRNA modifications (U34-TM) in establishing context-specific proteomes that drive WNT-dependent intestinal tumorigenesis and breast cancer metastasis. Remarkably, we observed that U34-TM enzymes (including Elp3, Alkbh8, and Ctu1/2) are upregulated in neutrophils isolated from breast tumor-bearing mice, as compared to those from tumor-free (naïve) controls.
In this study, we hypothesized that U34-TM supports translational reprogramming in neutrophils during breast cancer progression. To investigate this, we generated a neutrophil-specific U34-TM loss-of-function model by crossing Elp3lox/lox mice with the Mrp8-Cre strain. Our findings demonstrate that Elp3 depletion significantly reduced neutrophil numbers in the lungs and spleens of tumor-bearing mice. Importantly, this correlated with a marked reduction in metastatic burden in PyMT mice. Unexpectedly, the loss of Elp3 also led to a pronounced decrease in both the number and size of primary breast tumors.
In parallel, we observed that Elp3 deficiency alters mitochondrial morphology and modulates the metabolic state of TANs.
These results collectively highlight a pivotal role for U34-TM in regulating neutrophil function during breast cancer progression. Our research aims to further dissect the immune regulatory networks driving the anti-tumoral response and to characterize the translational changes in neutrophils within the tumor microenvironment.
