Glioblastoma induces the recruitment and differentiation of hybrid neutrophils from skull bone marrow
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE271618 | GEO | 2024/07/06
REPOSITORIES: GEO
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Project description:Tumor-associated neutrophils (TANs) can be conditioned to become “N2” pro-tumorigenic neutrophils in the tumor microenvironment. TANs have been shown to acquire N2 features and promote multiple aspects of tumor growth in mouse models of many cancers, including non-small cell lung cancer. We developed a novel mouse model for lung squamous cell carcinoma (LSCC): Rosa26LSL-Sox2-IRES-GFP;Nkx2-1fl/fl;Lkb1fl/fl (SNL). SNL mice develop tumors with short latency of ~3 months and SNL tumors have high neutrophil infiltration similar to other LSCC mouse models. We employed this novel model and single-cell RNA-sequencing to profile TANs in SNL lung tumors in comparison to peripheral blood neutrophils (PBNs) from tumor-bearing SNL mice.
2018-10-16 | GSE118245 | GEO
Project description:Neutrophils are the most abundant circulating leucocytes and constitute an essential component of innate immunity. Although their role in cancer development is still poorly defined, pro- or anti-tumor properties have been attributed to tumor-associated neutrophils (TANs), suggesting major functional diversities. In this study, we focused on the mechanisms involved in neutrophil accumulation within the lung tumor mass. We first identified G-CSF as an inducer of the high-affinity glucose transporter Glut1 in neutrophils, increasing their survival ex vivo. In a genetically engineered mouse model of lung adenocarcinoma, we report that TANs have an increased Glut1 expression and glucose metabolism compared to normal neutrophils. To elucidate the impact of glucose uptake on TANs, we used an in vivo strategy based on two recombinases, Flp to initiate lung tumors, and Cre to delete Glut1 specifically in neutrophils. We demonstrate that the loss of Glut1 decreases the SiglecFhigh TAN subpopulation by accelerating neutrophil turnover in tumors through reduced survival and augmented recruitment. Accelerated TAN turnover led to a decreased tumor growth and synergized with radiotherapy. Altogether, our results demonstrate the importance of Glut1 for neutrophil turnover, which directly affects the pro- versus anti-tumor balance within the tumor. These results also suggest that metabolic vulnerabilities can be exploited to target tumor-supportive neutrophil populations.
2021-03-18 | GSE140153 | GEO
Project description:The role of neutrophils in tumor is still controversial and largely unknown. We previously identified an anticancer tumor microenvironment from mice lacking Smad3, but the underlying mechanism is still largely unclear. Interestingly, depletion of neutrophils largely suppressed the anticancer phenotype of Smad3-KO mice against syngeneic murine Lewis lung carcinoma (LLC). Here, we discovered that Smad3 is essential for promoting N1/N2 polarization of the tumor_x0002_associated neutrophils (TANs) in lung carcinoma. We found that Smad3 deficiency dramatically increased N1 TANs associated with an anticancer phenotype in mice and detected a negative correlation between Smad3 activation and anticancer N1 associated with a higher mortality of NSCLC. By conducting a neutrophil-specific single-cell RNA-sequencing, we uncovered that Smad3 is essential for completing the N1/N2 polarization of TANs, whereas N1 will be the dominated phenotype in the Smad3-KO TME by analyzing the developmental pathways of TANs with pseudo-time at transcriptome level. Mechanistically, direct binding of Smad3 on the developmental genes in neutrophils under cancer condition was evidenced by ChIP-sequencing at genomic level. Importantly, both neutrophil-specific and pharmaceutical inhibition of Smad3 effectively enhanced the anticancer activity of human and murine TANs, thereby suppressing the progression of lung carcinoma in vivo. Thus, Smad3 may represent a precision therapeutic target for enhancing the anticancer activity of TANs via blocking N1/N2 polarization in NSCLC. in C57BL6 (wild-type) and Smad3-deficient (Smad3-/- ) mice and submitted for cell encapsulation and library construction by Chromium controller with 5’ expression kit (10x genomics)
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Project description:It is becoming increasingly clear that tumor-associated neutrophils (TANs) play an important role in cancer biology, through direct impact on tumor growth and by recruitment of other cells types into the tumor. The function of neutrophils in cancer has been the subject of seemingly contradicting reports, pointing toward a dual role played by TANs in tumor progression. The existence of multiple neutrophil subsets, as well as phenotypic modulation of the neutrophils by various factors in the tumor microenvironment, has been shown. TGFβ plays a significant role in the determination of neutrophils' phenotype, by shifting the balance from an antitumor (N1) toward a more permissive (N2) phenotype. The full range of mechanisms responsible for the pro- vs. antitumor effects of TANs has not yet been elucidated. Therefore, the ability to identify the different neutrophil subpopulations in the tumor is critical in order to understand TANs evolution and contribution throughout tumor progression. Using a transcriptomic approach, we identified alternations in gene expression profile following TGFβ inhibition. We show that N1 and N2 TANs represent distinct subpopulations with different transcriptional signatures and both differ from naive bone marrow neutrophils. The analysis highlights a clear difference in pathways involved in neutrophil function such as cytoskeletal organization and antigen presentation, as well as alterations in chemokine profile, eventually affecting their effect on tumor cells and tumor growth. These data highlights several potential new pathways and mechanisms by which neutrophils can influence both the tumor cells and the adaptive immune system.
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Project description:We performed RNA-seq analysis of tumor infiltrating neutrophils from C57BL/6 mice and iNKT deficient Traj18-/- mice to understand the role of iNKT cells in affecting phenotype and functions of neutrophils in CRC. We observed that TANs from B6 animals were enriched for transcripts of chemokines and inflammation as well as of immune suppression. These data suggest that iNKT cells condition the phenotype of TANs.
2023-04-16 | E-MTAB-12278 | biostudies-arrayexpress
Project description:We found different expression between glycolytic enzymes and TCA pathway in bone marrow neutrophils following LPS treatment, using RNAseq. This enable us to uncover the important role of glycolysis in activated neutrophils and the effect of HIF-1alpha on this pathway
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Project description:Necrosis is commonly found in various solid tumors and predicts worse outcome. Chronic ischemia can initiate tumor necrosis, but how the damaged tissue further expands is unclear. Previous studies found that neutrophils associate with necrosis and could contribute to necrosis development in glioblastoma (GBM) by transferring myeloperoxidase (MPO)-containing granules into tumor cells and inducing tumor cell ferroptosis. How the neutrophilic granule transfer occurs is unknown. Here, through an unbiased small molecule screen, we found that statins can inhibit neutrophil-induced tumor cell death by blocking the neutrophilic content transfer into tumor cells. Surprisingly, we found that neutrophils are engulfed by tumor cells before they are fragmented and release the MPO-containing contents in tumor cells. This process involves LC3-associated phagocytosis (LAP) and can be blocked by inhibiting the Vps34-UVRAG-containing PI3K complex. Inhibition of MPO or depletion of Vps34 in an orthotopic xenograft GBM mouse model reduced necrosis formation and allowed tumor-bearing mice to survive longer. Therefore, this study revealed that the neutrophilic granule transfer involves LAP-mediated neutrophil internalization, which then triggers tumor ferroptotic cell death in glioblastoma. Blocking this process may improve prognosis of GBM.
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Project description:We employed GeneChip analysis to investigate the global gene expression profiles of neutrophils from BM Gr-1high/CD48– neutrophils were sorted from the BM of C57BL/6 mice by FACS in two independent experiments
2014-01-06 | E-GEOD-53826 | biostudies-arrayexpress
Project description:The role of myeloid cells in supporting cancer growth is well established. Most work has focused on myeloid-derived suppressor cells (MDSC) that accumulate in tumor-bearing animals, but tumor-associated neutrophils (TAN) are also known to be capable of augmenting tumor growth. However, little is known about their evolution, phenotype, and relationship to naive neutrophils (NN) and to the granulocytic fraction of MDSC (G-MDSC). In the current study, a transcriptomics approach was used in mice to compare these cell types. Our data show that the three populations of neutrophils are significantly different in their mRNA profiles with NN and G-MDSC being more closely related to each other than to TAN. Structural genes and genes related to cell-cytotoxicity (i.e. respiratory burst) were significantly down-regulated in TAN. In contrast, many immune-related genes and pathways, including genes related to the antigen presenting complex (e.g. all six MHC-II complex genes), and cytokines (e.g. TNF-a, IL-1-a/b), were up-regulated in G-MDSC, and further up-regulated in TAN. Thirteen of the 25 chemokines tested were markedly up-regulated in TAN compared to NN, including striking up-regulation of chemoattractants for T/B-cells, neutrophils and macrophages. This study characterizes different populations of neutrophils related to cancer, pointing out the major differences between TAN and the other neutrophil populations. Various types of myeloid cells have been shown to promote tumor progression by direct immune suppression and by production of angiogenic factors, matrix-degrading enzymes, or growth factors. In untreated tumors, neutrophils have been reported to produce angiogenic factors and matrix-degrading enzymes, support the acquisition of a metastatic phenotype, and suppress the anti-tumor immune response. Neutrophils, like all other leukocytes, move into tissues from the blood under the influence of specific chemokines (e.g. KC/CXCL-1, MIP-2a/CXCL-2 and GCP-2/CXCL-6), cytokines (e.g. TNFa and IFN-x), and cell adhesion molecules located on their own surface (e.g. CD11b) and on the surface of endothelial cells (e.g. selectins, ICAM-1 and PECAM-1). When they traffic into tumors, they are referred to as TAN. In mice, TAN can be defined by the specific surface markers CD11b and Ly6G with low expression of macrophage markers such as F4/80. Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immune suppressive cells that are produced excessively in cancer. They comprise at least two subsets -granulocytic (Ly6G+, G-MDSC) and monocytic cells (Ly6C+, M-MDSC), potentially with different immunosuppressive properties. It has been previously shown that MDSC can enter tumors and differentiate to mature macrophages (TAM) or neutrophils (TAN). However, since no definitive markers have been established, it is unknown whether intratumoral N2 neutrophils (N2 TAN) are granulocytic MDSC from spleen that are attracted to the tumor or if they are typical blood-derived neutrophils that are then converted to an N2 phenotype by the tumor microenvironment, specifically by the high local concentrations of TGF-b. The purpose of this study was to use a transcriptomics approach to gain further information about TANs by comparing the RNA profile of these cells to naive bone-marrow neutrophils (NN) and to the granulocytic fraction of myeloid derived suppressor cells (G-MDSC). We examined which pathways and gene-groups varied amongst these 3 populations of neutrophils and performed a detailed analysis on pathways related to the main functions of neutrophils, such as respiratory burst, granule proteins, phagocytosis, apoptosis, structural genes, antigen presentation and specific immune effects. Our data defines TAN as a unique population of neutrophils, quite distinct from both NN and G-MDSC.
2013-01-04 | E-GEOD-43254 | biostudies-arrayexpress
Project description:Analysis of cell membrane-enriched proteins of mouse polymorphonuclear neutrophils. Further related data are present in project <a href="http://www.ebi.ac.uk/pride/archive/projects/PXD002244">PXD002244</a>.
2015-10-09 | PXD003015 | Pride