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DRUG-seq of high-density neutrophils (HDNs), mature low-density neutrophils (M-LDN), and immature low-density neutrophils (IM-LDN) in patients with colorectal cancer

ABSTRACT: High-density neutrophils (HDNs), mature low-density neutrophils (M-LDN), and immature low-density neutrophils (IM-LDN) were isolated from peripheral blood of nine treatment-naïve colorectal cancer (CRC) patients with histologically confirmed diagnoses, followed by gene expression profiling of these neutrophil subsets using Digital RNA with pertUrbation of Genes (DRUG) sequencing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302902 | GEO | 2025/11/02

REPOSITORIES: GEO

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DRUG-seq of high-density neutrophils (HDNs), mature low-density neutrophils (M-LDN), and immature low-density neutrophils (IM-LDN) in patients with colorectal cancer

Project description:DRUG-seq of high-density neutrophils (HDNs), mature low-density neutrophils (M-LDN), and immature low-density neutrophils (IM-LDN) in patients with colorectal cancer

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S. aureus drives expansion of low density neutrophils in the diabetic host

Project description:Abstract S. aureus is a major opportunistic pathogen infecting patients with diabetes. Increased mortality was observed following IV S. aureus infection in diabetic mice compared to non-diabetic controls, correlating with increased numbers of low density neutrophils (LDNs) and neutrophil extracellular traps (NETs). LDN development is dependent on TGFβ, which was more activated in the diabetic host. Neutralization of TGFβ, or the integrin responsible for its activation α5β8, reduced numbers of LDNs and improved survival. Comparison of high and low density neutrophils identified PTEN signaling as a central regulator of LDN NET release. Inhibition of PTEN improved survival and decreased NET production in infected diabetic mice. MEDI4893*, a monoclonal antibody that neutralizes alpha toxin (AT) in development for prevention of S. aureus infection, was able to block TGFβ activation, reduce LDNs and NETs, and significantly improve survival. Our data identify a population of neutrophils in infected diabetic mice which correlated with decreased survival and increased NET production. Targeting a single virulence factor of S. aureus prevented emergence of the LDN population and improved survival, supporting potential use of pathogen specific antibodies for treating diabetic infections.

2019-04-26 | PXD012176 | Pride

Metabolic flexibility and expression of CD98 define the low density neutrophils mobilised in response to G-CSF

Project description:Low density neutrophils (LDN) co-purify with mononuclear cells during density-gradient separation of peripheral blood. LDN are rarely detected in healthy individuals but appear in the peripheral blood (PB) of patients with inflammatory diseases, malignancies and in individuals treated with granulocyte colony-stimulating factor (G-CSF). Using human G-CSF mobilized LDN, this study reveals that LDN are transcriptionally, proteomically and metabolically distinct from other neutrophils. Single Cell RNAseq analysis reveals that LDN from these donors comprise one major population, with multiple interrelated transcriptional states, representing the continuum of neutrophil maturation. LDN can engage both glycolysis and mitochondrial respiration to meet energy demands, which affords increased metabolically flexibility in the nutrient perturbed tissue environments found in tumours and inflammatory diseases. This study also identifies upregulated expression of CD98, a transporter for branch chain and aromatic amino acids, as a cell surface marker for LDN in peripheral blood. CD98 may contribute to the functional properties of LDNs and represents a useful phenotypic marker.

2022-12-19 | PXD023952 | Pride

Immature low-density neutrophils exhibit metabolic flexibility that facilitates breast cancer liver metastasis

Project description:Neutrophils play a key role in the control of metastatic progression. Neutrophils are phenotypically heterogeneous and can exert either anti- or pro-metastatic functions. Here, we demonstrate that tumor cells capable of forming liver metastases induce an accumulation of neutrophils in the peripheral blood and liver parenchyma. Cancer cell-derived G-CSF, in concert with other factors, mobilizes immature low-density neutrophils that promote liver metastasis. In contrast, mature high-density neutrophils inhibit the formation of liver metastases. Transcriptomic and metabolomic analyses of high- and low- density neutrophils reveal engagement of numerous metabolic pathways specifically in low-density neutrophils. Low-density neutrophils exhibit enhanced global bioenergetic capacity, through their ability to engage mitochondrial-dependent ATP production, and remain capable of executing pro-metastatic neutrophil functions, including NETosis, under nutrient-deprived conditions. Together, these data reveal that distinct pro-metastatic neutrophil populations exhibit a high degree of metabolic flexibility, which facilitates metastatic progression and the formation of liver metastases.

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Increased Inflammatory Low-Density Neutrophils in Morbid Obesity: Gene Expression and Effect of Bariatric Surgery

Project description:Background: Low-density neutrophils (LDN) are increased in several inflammatory diseases, and may also play a role in low-grade chronic inflammation in obesity. Yet their role in obesity or the effect of bariatric surgery-induced weight loss is unknown. Methods: We compared circulating LDN, their function, and gene expression between morbidly obese patients (MOP; BMI > 40 Kg/m2) and normal-weight controls (NWC; BMI < 25 Kg/m2) in a case-control study. Additionally, in a prospective longitudinal study, we measure changes in the frequency of LDN before and after bariatric surgery, and tested possible associations with metabolic and inflammatory parameters. Findings: LDN and inflammatory markers were significantly increased in MOP (n=27) compared to NWC (n=20). Transcriptome analysis of LDN from MOP showed an increased neutrophil-related gene expression signature associated with inflammation, neutrophil activation, and immunosuppressive function. However, LDN did not suppress T cells proliferation and produced low levels of ROS. Circulating LDN in MOP significantly decreased after surgery in parallel with BMI, metabolic syndrome and inflammatory markers. Interpretation: Obesity increases LDN with inflammatory gene signature. Bariatric surgery has anti-inflammatory effect including reduction of LDN. Gene expression and phenotype suggest that LDN represent a neutrophil subset that may be associated with obesity-associated chronic inflammation that promotes co-morbidities.

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Immature low-density neutrophils exhibit metabolic flexibility that facilitates breast cancer liver metastasis

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Staphylococcus aureus drives expansion of low-density neutrophils in diabetic mice

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Real-time quantitative PCR analysis of human low-density (LDNs) and normal-density neutrophils (NDNs)

Project description:Real-time quantitative PCR analysis of human low-density (LDNs) and normal-density neutrophils (NDNs)

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