Syntaphilin regulates neutrophil migration in cancer

Pathologically activated neutrophils (PMN) with immune suppressive activity - myeloid-derived suppressor cells (PMN-MDSC) - play a critical role in regulation of tumor progression. They were implicated in promotion of tumor metastases by contributing to pre-metastatic niche formation. This effect was facilitated by enhanced spontaneous migration of PMN in early stage cancers. The molecular mechanisms underpinning this phenomenon remained unclear. We found that syntaphilin (SNPH), a cytoskeletal protein previously known for anchoring mitochondria to the microtubule in neurons and tumor cells, could regulate migration of PMN. Expression of SNPH was decreased in PMN from tumor bearing mice and cancer patients as compared to PMN from tumor-free mice and healthy donors, respectively. Deletion of SNPH increased spontaneous migration of PMN and promoted tumor metastasis. Mechanistically, deletion of SNPH increased the speed and distance travelled by mitochondria, elevated rates of oxidative phosphorylation and glycolysis, and increased generation of adenosine. Thus, our study reveals a molecular mechanism regulating increased migratory activity of PMN during cancer progression and suggests novel targeting opportunity. RNA-seq experiment in SNPH WT and KO cells