Abstract
Necrosis in solid tumors is commonly associated with poor prognostic but how these lesions expand remains unclear. Studies have found that neutrophils associate with and contribute to necrosis development in glioblastoma by inducing tumor cell ferroptosis through transferring myeloperoxidase-containing granules. However, the mechanism of neutrophilic granule transfer remains elusive. We performed an unbiased small molecule screen and found that statins inhibit neutrophil-induced tumor cell death by blocking the neutrophilic granule transfer. Further, we identified a novel process wherein neutrophils are engulfed by tumor cells before releasing myeloperoxidase-containing contents into tumor cells. This neutrophil engulfment is initiated by integrin-mediated adhesion, and further mediated by LC3-associated phagocytosis (LAP), which can be blocked by inhibiting the Vps34-UVRAG-RUBCN-containing PI3K complex. Myeloperoxidase inhibition or Vps34 depletion resulted in reduced necrosis formation and prolonged mouse survival in an orthotopic glioblastoma mouse model. Thus, our study unveils a critical role for LAP-mediated neutrophil internalization in facilitating the transfer of neutrophilic granules, which in turn triggers tumor cell death and necrosis expansion. Targeting this process holds promise for improving glioblastoma prognosis.
Overview
- The study investigates the role of neutrophils in necrosis development in glioblastoma and identifies a novel process for neutrophil internalization in facilitating the transfer of neutrophilic granules, which triggers tumor cell death and necrosis expansion. The study tests the hypothesis that neutrophilic granule transfer is a critical process in necrosis development in glioblastoma and that targeting this process can improve glioblastoma prognosis. The methodology used for the experiment includes an unbiased small molecule screen, mouse models, and imaging techniques. The primary objective of the study is to identify the mechanism of neutrophilic granule transfer and its role in necrosis development in glioblastoma and to test the hypothesis that targeting this process can improve glioblastoma prognosis.
Comparative Analysis & Findings
- The study compares the outcomes observed under different experimental conditions, including the effects of statins on neutrophil-induced tumor cell death and the role of LC3-associated phagocytosis (LAP) in neutrophil internalization. The results show that statins inhibit neutrophil-induced tumor cell death by blocking neutrophilic granule transfer, and that LAP-mediated neutrophil internalization is a critical process in facilitating the transfer of neutrophilic granules, which triggers tumor cell death and necrosis expansion. The study also identifies a novel process wherein neutrophils are engulfed by tumor cells before releasing myeloperoxidase-containing contents into tumor cells, which is initiated by integrin-mediated adhesion and further mediated by LAP. The key findings of the study support the hypothesis that neutrophilic granule transfer is a critical process in necrosis development in glioblastoma and that targeting this process can improve glioblastoma prognosis.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice, as they identify a novel process for neutrophil internalization in facilitating the transfer of neutrophilic granules, which triggers tumor cell death and necrosis expansion. The study also identifies a potential therapeutic target for improving glioblastoma prognosis. However, the study has limitations, such as the use of mouse models and the need for further validation in human studies. Future research directions could include investigating the role of neutrophils in necrosis development in other solid tumors, exploring the use of LAP inhibitors as a therapeutic target, and investigating the potential side effects of LAP inhibitors.