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Published on: February 16, 2020
Syntaphilin Regulates Neutrophil Migration in Cancer
Shuyu Fu1, Hui Deng1, Irene Bertolini1
1Immunology, Microenvironment and Metastasis Program, Wistar Institute, Philadelphia, Pennsylvania.
Abstract:
Pathologically activated neutrophils (PMN) with immunosuppressive activity, which are termed myeloid-derived suppressor cells (PMN-MDSC), play a critical role in regulating tumor progression. These cells have been implicated in promoting tumor metastases by contributing to premetastatic niche formation. This effect was facilitated by enhanced spontaneous migration of PMN from bone marrow to the premetastatic niches during the early-stage of cancer development. The molecular mechanisms underpinning this phenomenon remained unclear. In this study, 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 patients with cancer as compared with PMN from tumor-free mice and healthy donors, respectively. In Snph-knockout (SNPH-KO) mice, spontaneous migration of PMN was increased and the mice showed increased metastasis. Mechanistically, in SNPH-KO mice, the speed and distance travelled by mitochondria in PMN was increased, rates of oxidative phosphorylation and glycolysis were elevated, and generation of adenosine was increased. Thus, our study reveals a molecular mechanism regulating increased migratory activity of PMN during cancer progression and suggests a novel therapeutic targeting opportunity.
Insights
Syntaphilin (SNPH) regulates neutrophil migration in cancer. Decreased SNPH increases myeloid-derived suppressor cell migration, promoting tumor metastasis and suggesting new therapeutic targets.
Area of Science:
- Immunology
- Cancer Biology
- Cell Biology
Background:
- Pathologically activated neutrophils, termed myeloid-derived suppressor cells (PMN-MDSC), promote tumor progression and metastasis.
- PMN-MDSC facilitate premetastatic niche formation through enhanced migration from bone marrow.
- The molecular mechanisms controlling PMN migration in cancer remain largely unknown.
Purpose of the Study:
- To investigate the role of syntaphilin (SNPH) in regulating neutrophil migration.
- To elucidate the molecular mechanisms by which SNPH influences PMN migration and metastasis.
Main Methods:
- Analysis of SNPH expression in neutrophils from tumor-bearing and healthy individuals/mice.
- Assessment of PMN migration, metastasis, mitochondrial dynamics, and metabolic activity in syntaphilin-knockout (SNPH-KO) mice.
- Measurement of adenosine generation in PMN.
Main Results:
- SNPH expression is decreased in PMN from tumor-bearing mice and cancer patients.
- SNPH-KO mice exhibit increased spontaneous PMN migration and enhanced tumor metastasis.
- In SNPH-KO mice, PMN show increased mitochondrial transport, elevated oxidative phosphorylation and glycolysis, and heightened adenosine production.
Conclusions:
- Syntaphilin (SNPH) is a key regulator of PMN migration.
- Reduced SNPH expression contributes to increased PMN migration and metastasis in cancer.
- Targeting SNPH presents a potential therapeutic strategy for inhibiting cancer progression.
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