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Tumor-stroma interaction between RCC cell lines and lung stroma in mouse xenografts

ABSTRACT: The leading cause of death in human patients with metastatic renal cell carcinoma (RCC) and malignant cancer in general is the dissemination of the primary tumor to secondary sites. The mechanisms by which RCC colonize the lung microenvironment during metastasis remain largely unknown. To investigate the mechanisms of lung colonization by tumor cells, we grafted human RCC cells with different lung metastatic activities in mice. Gene expression profiling of the mouse lung stromal compartment revealed a gene signature enriched for neutrophil-specific functions, induced preferentially by poorly metastatic cells. Analysis of the gene expression patterns in tumor cells and clinical specimens showed an inverse correlation between metastatic activity and the levels of a number of chemokines, including CXL5 ad IL8. Enforced depletion of CXCL5 and IL8 in tumor cells allowed us to establish a functional link between lung neutrophil infiltration, the secretion of chemokines by cancer cells and metastatic activity. Finally, we showed that human neutrophils displayed a higher cytotoxic activity toward poorly metastatic cells relative to highly metastatic cells. Together, these results support a model in which neutrophils recruited to the lung by tumor-secreted chemokines build an antimetastatic barrier and loss of those neutrophil chemokines in tumor cells is a critical rate-limiting step during lung metastatic seeding.

ORGANISM(S): Mus musculus

PROVIDER: GSE29688 | GEO | 2012/05/30

SECONDARY ACCESSION(S): PRJNA141105

REPOSITORIES: GEO

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Tumor-stroma interaction between RCC cell lines and lung stroma in mouse xenografts

Project description:The leading cause of death in human patients with metastatic renal cell carcinoma (RCC) and malignant cancer in general is the dissemination of the primary tumor to secondary sites. The mechanisms by which RCC colonize the lung microenvironment during metastasis remain largely unknown. To investigate the mechanisms of lung colonization by tumor cells, we grafted human RCC cells with different lung metastatic activities in mice. Gene expression profiling of the mouse lung stromal compartment revealed a gene signature enriched for neutrophil-specific functions, induced preferentially by poorly metastatic cells. Analysis of the gene expression patterns in tumor cells and clinical specimens showed an inverse correlation between metastatic activity and the levels of a number of chemokines, including CXL5 ad IL8. Enforced depletion of CXCL5 and IL8 in tumor cells allowed us to establish a functional link between lung neutrophil infiltration, the secretion of chemokines by cancer cells and metastatic activity. Finally, we showed that human neutrophils displayed a higher cytotoxic activity toward poorly metastatic cells relative to highly metastatic cells. Together, these results support a model in which neutrophils recruited to the lung by tumor-secreted chemokines build an antimetastatic barrier and loss of those neutrophil chemokines in tumor cells is a critical rate-limiting step during lung metastatic seeding. Total 12 samples are analysed from two cell lines (SN12C and LM2) and Normal tissue. There are four biological replicates for each cell line and four biological replicates from normal lung tissue (as reference).

2012-05-29 | E-GEOD-29688 | biostudies-arrayexpress

Neutrophil expression array

Project description:Primary tumors have been shown to prepare distal organs for later colonization of metastatic cells by stimulating organ-specific infiltration of bone marrow-derived cells. Here we demonstrate that neutrophils accumulate in the lung prior to the arrival of metastatic cells in mouse models of breast cancer. Tumor-entrained neutrophils (TENs) inhibit metastatic seeding in the lungs by generating H2O2, and tumor-secreted CCL2 is a critical mediator of optimal anti-metastatic entrainment of G-CSF-stimulated neutrophils. TENs are present in the peripheral blood of breast cancer patients prior to surgical resection but not in healthy individuals. Thus, while tumor-secreted factors contribute to tumor progression at the primary site, they concomitantly induce a neutrophil-mediated inhibitory process at the metastatic site. This experiment was designed to compare the RNA expression profile in resting (control) neutrophils vs. that of TENs (neutrophils purified from tumor-bearing mice). In addition, we also compared the expression profiles of cultured neutrophils in vitro and treated with CCL2, CCL5 and GCSF.

2011-07-25 | GSE30887 | GEO

Pre-metastatic expression array day 7

Project description:Primary tumors have been shown to prepare distal organs for later colonization of metastatic cells by stimulating organ-specific infiltration of bone marrow-derived cells. Here we demonstrate that neutrophils accumulate in the lung prior to the arrival of metastatic cells in mouse models of breast cancer. Tumor-entrained neutrophils (TENs) inhibit metastatic seeding in the lungs by generating H2O2, and tumor-secreted CCL2 is a critical mediator of optimal anti-metastatic entrainment of G-CSF-stimulated neutrophils. TENs are present in the peripheral blood of breast cancer patients prior to surgical resection but not in healthy individuals. Thus, while tumor-secreted factors contribute to tumor progression at the primary site, they concomitantly induce a neutrophil-mediated inhibitory process at the metastatic site. To follow the earliest transcriptional changes in pre-metastatic tissues, we orthotopically injected 4T1 cells into the mammary fat pad of female nude mice. Control mice were orthotopically injected with PBS. 7 days post tumor engraftment, the mice were sacrificed and thoroughly perfused with ice cold PBS, and lung and liver samples were flash frozen in liquid nitrogen. Following RNA extraction, the lung and liver RNA samples were analyzed on MOE430A2 Affymetrix arrays using R/Bioconductor software.

2011-07-25 | GSE30885 | GEO

Analysis of blood myelomonocytic cells from RCC patients

Project description:Myelomonocytic cells (i.e., monocytes or macrophages) play a key role in tumor progression as revealed by numerous mice tumor model studies. However, their contribution in human tumor progression is not well-studied. Using Renal Cell Carcinoma (RCC) as a model for human cancer, we performed a transcriptomal profiling of blood monocytes from RCC patients to investigate the contribution of these cells in cancer progression. As compared to monocytes from healthy donors (Mo), transcriptome analysis of monocytes from RCC patients (RCC-Mo) showed a distinct gene expression signature consisting of cytokines, chemokines and various inflammation-related genes. Validation of these genes by qPCR as well as other functional assays indicated RCC-Mo possess an inflammatory and tumor promoting phenotype. Blood monocytes from RCC patients (with early or metastatic disease) or healthy donors (controls) were isolated, and then differential gene expression was detected with Limma.

2014-10-30 | E-GEOD-38424 | biostudies-arrayexpress

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.

2019-06-26 | GSE123669 | GEO

Lipopolysaccharide-stimulated neutrophils

Project description:Neutrophil gene transcription following lipopolysaccharide exposure. Microarray analysis of lipopolysaccharide-treated human neutrophils. Neutrophils respond to infection by degranulation, release of reactive oxygen intermediates, and secretion of chemokines and cytokines; however, activation of neutrophil transcriptional machinery has been little appreciated. Recent findings suggest that gene expression may represent an additional neutrophil function after exposure to lipopolysaccharide (LPS). We performed microarray gene expression analysis of 4,608 mostly nonredundant genes on LPS-stimulated human neutrophils. Analysis of three donors indicated some variability but also a high degree of reproducibility in gene expression. Twenty-eight verifiable, distinct genes were induced by 4 h of LPS treatment, and 13 genes were repressed. Genes other than cytokines and chemokines are regulated; interestingly, genes involved in cell growth regulation and survival, transcriptional regulation, and interferon response are among those induced, whereas genes involved in cytoskeletal regulation are predominantly repressed. In addition, we identified monocyte chemoattractant protein-1 as a novel LPS-regulated chemokine in neutrophils. Included in these lists are five clones with no defined function. These data suggest molecular mechanisms by which neutrophils respond to infection and indicate that the transcriptional potential of neutrophils is greater than previously thought.

2010-06-05 | E-GEOD-105 | biostudies-arrayexpress

Expression profiling of CD45- lung tumor cells

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 | GSE140154 | GEO

Expression profiling of lung neutrophils

2021-03-18 | GSE140153 | GEO

RNA sequencing of blood and lung neutrophils from tumor-bearing mice

Project description:To investigate the difference among neutrophils circulating in the blood, and those infiltrating in the metastatic organ, we isolated peripheral blood (PB) and lung neutrophils from AT3 tumor-bearing mice. Total RNA was isolated from neutrophils and the transcriptional profiles of neutrophils were analyzed by RNA seq.

2022-12-12 | E-MTAB-12365 | biostudies-arrayexpress

Murine Bone Marrow Stromal Cell Response to Granulocyte Colony-Stimulating Factor

Project description:Neutrophil homeostasis is maintained, in part, by the regulated release of neutrophils from the bone marrow. Constitutive expression of the chemokine CXCL12 by bone marrow stromal cells provides a key retention signal for neutrophils in the bone marrow through activation of its receptor CXCR4. Herein, we show that the ELR chemokines CXCL1 and CXCL2 are constitutively expressed by bone marrow endothelial cells and osteoblasts, and CXCL2 expression is induced in endothelial cells during granulocyte colony-stimulating factor (G-CSF)-induced neutrophil mobilization. Neutrophils lacking CXCR2, the receptor for CXCL1 and CXCL2, are preferentially retained in the bone marrow, reproducing a myelokathexis phenotype. Transient disruption of CXCR4 failed to mobilize CXCR2 neutrophils. However, doubly deficient neutrophils (CXCR2-/- CXCR4-/-) displayed constitutive mobilization, showing that CXCR4 plays a dominant role. Collectively, these data suggest that CXCR2 signaling is a second chemokine axis that interacts antagonistically with CXCR4 to regulate neutrophil release from the bone marrow. We used gene expression microarrays to determine the changes in osteoblasts and bone marrow endothelial cells after G-CSF treatment. 3 untreated and G-CSF-treated osteoblast samples and 4 untreated and G-CSF-treated endothelial samples.

2010-07-14 | E-GEOD-22925 | biostudies-arrayexpress

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