LC3-associated phagocytosis of neutrophils triggers tumor ferroptotic cell death in glioblastoma.

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.

Ferroptosis in glioma therapy: advancements in sensitizing strategies and the complex tumor-promoting roles.

Ferroptosis, an iron-dependent form of non-apoptotic regulated cell death, is induced by the accumulation of lipid peroxides on cellular membranes. Over the past decade, ferroptosis has emerged as a crucial process implicated in various physiological and pathological systems. Positioned as an alternative modality of cell death, ferroptosis holds promise for eliminating cancer cells that have developed resistance to apoptosis induced by conventional therapeutics. This has led to a growing interest in leveraging ferroptosis for cancer therapy across diverse malignancies. Gliomas are tumors arising from glial or precursor cells, with glioblastoma (GBM) being the most common malignant primary brain tumor that is associated with a dismal prognosis. This review provides a summary of recent advancements in the exploration of ferroptosis-sensitizing methods, with a specific focus on their potential application in enhancing the treatment of gliomas. In addition to summarizing the therapeutic potential, this review also discusses the intricate interplay of ferroptosis and its potential tumor-promoting roles within gliomas. Recognizing these dual roles is essential, as they could potentially complicate the therapeutic benefits of ferroptosis. Exploring strategies aimed at circumventing these tumor-promoting roles could enhance the overall therapeutic efficacy of ferroptosis in the context of glioma treatment.

Paraspeckle Protein NONO Promotes TAZ Phase Separation in the Nucleus to Drive the Oncogenic Transcriptional Program.

The Hippo pathway effector TAZ promotes cellular growth, survival, and stemness through regulating gene transcription. Recent studies suggest that TAZ liquid-liquid phase separation (LLPS) compartmentalizes key cofactors to activate transcription. However, how TAZ LLPS is achieved remains unknown. Here, it is shown that the paraspeckle protein NONO is required for TAZ LLPS and activation in the nucleus. NONO is a TAZ-binding protein. Their interaction shows temporal regulation parallel to the interaction between TAZ and TEAD as well as to the expression of TAZ target genes. NONO depletion reduces nuclear TAZ LLPS, while ectopic NONO expression promotes the LLPS. Accordingly, NONO depletion reduces TAZ interactions with TEAD, Rpb1, and enhancers. In glioblastoma, expressions of NONO and TAZ are both upregulated and predict poor prognosis. Silencing NONO expression in an orthotopic glioblastoma mouse model inhibits TAZ-driven tumorigenesis. Together, this study suggests that NONO is a nuclear factor that promotes TAZ LLPS and TAZ-driven oncogenic transcriptional program.

Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression.

Tumor necrosis commonly exists and predicts poor prognoses in many cancers. Although it is thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscure. Here, we show that necrosis in glioblastoma (GBM) involves neutrophil-triggered ferroptosis. In a hyperactivated transcriptional coactivator with PDZ-binding motif-driven GBM mouse model, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse brain tumors kill cocultured tumor cells. Mechanistically, neutrophils induce iron-dependent accumulation of lipid peroxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibition or depletion of myeloperoxidase suppresses neutrophil-induced tumor cell cytotoxicity. Intratumoral glutathione peroxidase 4 overexpression or acyl-CoA synthetase long chain family member 4 depletion diminishes necrosis and aggressiveness of tumors. Furthermore, analyses of human GBMs support that neutrophils and ferroptosis are associated with necrosis and predict poor survival. Thus, our study identifies ferroptosis as the underlying nature of necrosis in GBMs and reveals a pro-tumorigenic role of ferroptosis. Together, we propose that certain tumor damage(s) occurring during early tumor progression (i.e. ischemia) recruits neutrophils to the site of tissue damage and thereby results in a positive feedback loop, amplifying GBM necrosis development to its fullest extent.

Influence of surround proximity on induction of brown and darkness.

A bright white surround makes a yellow long-wavelength target look both browner and darker. We explored the parallel between these two types of induction by examining their dependence on the proximity of the bright surround to the target at two different time scales with 27 ms and 1 s stimulus durations. We assessed (a) brown induction by adjustment of target luminance to perceptual brown and yellow boundaries and (b) darkness induction by a successive matching procedure. We found that brown induction is a quick process that is robust even for 27 ms stimuli. For darkness induction, there was a strong, spatially localized surround proximity effect for the 27 ms stimuli and much weaker proximity effect for the 1 s stimuli. For brown induction, proximity effects were generally weaker but still showed relatively stronger localized proximity effects for 27 ms stimuli than for 1 s stimuli. For these stimuli, darkness induction predicts the relative pattern but not the magnitudes of brown induction. Both brown and darkness inductions show the operation of quick, spatially localized processes that are apparently superseded by other processes for extended stimulus presentations.