Red blood cell heme drives the generation of TAM-like macrophages with an immunocompromized phenotype
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE236439 | GEO | 2024/01/03
REPOSITORIES: GEO
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Project description:To study TAM phenotypes in hemorrhagic tumor tissues, we treated GFP-MC3 tumor-bearing mice with a single injection of immunotherapeutic anti-CD40 antibody on day 7 after tumor cell injection. Three days later, the tumors were collected for histology and genome-wide spatial analysis of mRNA expression. In both tumor samples, H&E histology visualized extensive tumor necrosis with RBCs extravasated into the necrotic areas of the tumors. Spatial gene-expression analysis allowed us to perform more detailed phenotyping, clearly discriminating zones of remaining viable cancer surrounded by hemorrhagic necrosis as evidenced by the enrichment of RBC-derived RNA (Hbb-bs). In these hemorrhagic regions, we found a Cd68 signal, confirming macrophage infiltration, superimposed by a strong signal for Hmox1 and Arg1. Like CD163 and Spp1 in human cancers, Arg1 is the archetypal marker gene for pro-cancerous and immunosuppressive TAMs in the mouse.
2024-01-03 | GSE237119 | GEO
Project description:Heme-activation of NRF2 is a strong anti-inflammatory signal in macrophages, and analyses in this study indicated that the expressed transcriptome in heme-TAMs was consistently enriched for NRF2 target genes. We have therefore delineated the role of NRF2 in a series of experiments with Nrf2 knockout BMDMs, leading to a locked NRF2-inactive state, and macrophages with a knockout of the cytoplasmic NRF2 capture protein KEAP1, leading to a locked NRF2-active state, irrespective of the presence or absence of heme. To demonstrate that activated NRF2 is sufficient to drive heme-TAM transformation, we analyzed Keap1 knockout macrophages.
2024-01-03 | GSE236997 | GEO
Project description:Tumor cells attract and dynamically interact with monocytes/macrophages to subvert their differentiation into tumor associated macrophages (TAMs), which mainly promote immunosuppression and neoplastic progression, but the pathways and microenvironmental cues governing their protumoral deviation are not completely understood. Thus, identifying molecular pathways responsible for TAM differentiation may provide new therapeutic targets to improve the efficacy of immunotherapy of cancer.
2021-08-09 | GSE171277 | GEO
Project description:To further analyze the change of microRNA(miRNA) between normal peritoneal macrophage(PEC) and TAM from early tumor(12 days after 4T1 cell injection) or TAM from late tumor(21 days after 4T1 cell injection) , we employed Agilent mouse microRNA microarray Rel 12.0 as a discovery platform to identify miRNAs Total RNA from peritoneal macrophage and TAM of early tumor (tumor formed for 12days after BALB/c mice injected wth 4T1 cell) or TAM of late tumor(tumor formed for 21days after BALB/c mice injected with 4T1 cell) were extracted and analyzed using Agilent mouse microRNA microarray platform, and changes of miRNA were screened out. Agilent mouse microRNA microarray is designed for the profiling of mouse miRNA .627 mouse miRNA and 39 mouse virus-related miRNA can be detected by our microRNA microarray.
2015-03-31 | E-GEOD-67408 | biostudies-arrayexpress
Project description:Wheat cultivars ‘TAM 111’ and ‘TAM 112’ have been dominantly grown in the Southern U.S. Great Plains for many years due to their excellent, yet variable, drought tolerance. To identify the molecular basis and genetic control of drought tolerance in these two landmark cultivars, RNA-seq analysis was conducted to compare gene expression difference in flag leaves under fully irrigated (wet) and water deficient (dry) conditions. Of the 122,017 gene sequences assembled, 2,254 genes showed significantly altered expression patterns under dry and wet conditions in the two cultivars. TAM 111 had 593 and 1,532 dry-wet differentially expressed genes (DEGs), and TAM 112 had 777 and 1,670 at heading and grain-filling stages, respectively. The two cultivars have 1,214 (53.9%) dry-wet DEGs in common, which agreed with their excellent adaption to drought, but 438 and 602 dry-wet DEGs were respectively shown only in TAM 111 and TAM 112 suggested that each may have a specific mechanism to cope with drought. Annotation of all 2,254 genes with dry-wet expression difference found 1,855 have functions related to biosynthesis, stress responses, defense responses, transcription factors and cellular components related to ion or protein transportation and signal transduction. Comparing hierarchical structure of biological processes, molecule functions and cellular components revealed the significant regulation differences between TAM 111 and TAM 112, particularly for genes of phosphorylation and adenyl ribonucleotide binding, and proteins located in nucleus and plasma membrane. Comparing gene expressions involved in responses to stresses of water deprivation, heat and oxidative, ABA-induced signal pathway and transcription regulation found TAM 112 have more specific dry-wet DEGs than TAM 111 with most of them up-regulated, indicating that TAM 112 is more active than TAM 111 in response to drought. In addition, 399 dry-wet DEGs with unknown functions included 258 genes encoding predicted uncharacterized proteins and 141 unannotated genes with no similar sequences identified in the databases. These may represent novel genes related to drought response in TAM 111 or TAM 112. This research thus revealed different drought-tolerance mechanisms in TAM 111 and TAM 112 and identified useful drought tolerance genes for wheat adaption.
2020-08-29 | GSE157033 | GEO
Project description:Gene expression was analyzed in peritoneal macrophages and TAM from mice injected with ID8 ovarian cancer cells intraperitoneally 5 and 21 days after tumor cell injection. Tumor-associated macrophages (TAM) have been shown to have important roles in the malignant progression of various cancers. However, macrophages also posses intrinsic tumoricidal activity and can promote the activity of cytotoxic lymphocytes, but they rapidly adopt an alternative phenotype within tumors, associated with immune-suppression and trophic functions that support tumor growth. The mechanisms that promote TAM polarization in the tumor-microenvironment remain poorly understood, these mechanisms may represent important therapeutic targets to block the tumor-promoting functions of TAM and restore their anti-tumor potential. Here we have characterized TAM in a mouse model of metastatic ovarian cancer. We show that ovarian cancer cells promote membrane-cholesterol efflux and the depletion of lipid rafts from macrophages. Increased cholesterol efflux promoted IL-4 mediated reprogramming while inhibiting IFNg-induced gene expression. These studies reveal an unexpected role for tumor-induced membrane-cholesterol efflux in driving the IL-4 signaling and the tumor-promoting functions of TAM, while rendering them refractory to pro-inflammatory stimuli. Thus, preventing cholesterol efflux in TAM could represent a novel therapeutic strategy to block pro-tumor functions and restore anti-tumor immunity.
2019-02-06 | GSE126098 | GEO
Project description:Background: The angiogenic response to ischemia restores perfusion so as to preserve tissue. A role for mesenchymal-to-endothelial transition in the angiogenic response is controversial. This study is to determine if resident fibroblasts contribute to angiogenesis. Methods: We utilized the murine model of hindlimb ischemia, and in vivo matrigel plug assay together with lineage tracing studies and single cell RNA-sequencing (scRNA-seq) to examine the transcriptional and functional changes in fibroblasts in response to ischemia. Results: Lineage tracing using Fsp1-Cre: R26R-EYFP mice revealed the emergence within the ischemic hindlimb of a small subset of YFP+ CD144+ CD11b- fibroblasts (E*cells) that expressed endothelial cell (EC) genes. Subcutaneous administration of matrigel in Fsp1-Cre: R26R-EYFP mice generated a plug that became vascularized within 5 days. Isolation of YFP+ CD11b- cells from the plug revealed a small subset of YFP+ CD144+ CD11b- E*cells which expressed EC genes. Pharmacological or genetic suppression of innate immune signaling reduced vascularity of the matrigel plug and abrogated the generation of these E*cells. These studies were repeated using human fibroblasts, with FACS analysis revealing that a small percentage of human fibroblasts that were induced to express EC markers in the matrigel plug assay. Pharmacological suppression or genetic knockout of inflammatory signaling abolished the generation of E*cells, impaired perfusion recovery and increased tissue injury after femoral artery ligation. To further characterize these E*cells, we performed scRNA-seq and revealed eight discrete clusters of cells expressing characteristic fibroblast genes, of which two clusters (C5 and C8) also expressed some EC genes. Ischemia of the hindlimb induced expansion of clusters C5 and C8. The C8 cells did not express CD144, nor did they form networks in Matrigel, but did generate angiogenic cytokines. The C5 fibroblasts most resembled E* cells in their expression of CD144 and their ability to form EC-like networks in Matrigel. Conclusion: Together, these studies indicate the presence of subsets of tissue fibroblasts which seem poised to contribute to the angiogenic response. The expansion of these subsets with ischemia is dependent upon activation of innate immune signaling, and contributes to recovery of perfusion and preservation of ischemic tissue.
2020-08-08 | GSE150383 | GEO
Project description:To further analyze the change of microRNA(miRNA) between normal peritoneal macrophage(PEC) and TAM from early tumor(12 days after 4T1 cell injection) or TAM from late tumor(21 days after 4T1 cell injection) , we employed Agilent mouse microRNA microarray Rel 12.0 as a discovery platform to identify miRNAs
2015-03-31 | GSE67408 | GEO
Project description:Gene expression was analyzed in peritoneal macrophages and TAM from mice injected with ID8 ovarian cancer cells intraperitoneally 28 days after tumor implantation. Tumor-associated macrophages (TAM) have been shown to have important roles in the malignant progression of various cancers. However, macrophages also posses intrinsic tumoricidal activity and can promote the activity of cytotoxic lymphocytes, but they rapidly adopt an alternative phenotype within tumors, associated with immune-suppression and trophic functions that support tumor growth. The mechanisms that promote TAM polarization in the tumor-microenvironment remain poorly understood, these mechanisms may represent important therapeutic targets to block the tumor-promoting functions of TAM and restore their anti-tumor potential. Here we have characterized TAM in a mouse model of metastatic ovarian cancer. We show that ovarian cancer cells promote membrane-cholesterol efflux and the depletion of lipid rafts from macrophages. Increased cholesterol efflux promoted IL-4 mediated reprogramming while inhibiting IFNg-induced gene expression. These studies reveal an unexpected role for tumor-induced membrane-cholesterol efflux in driving the IL-4 signaling and the tumor-promoting functions of TAM, while rendering them refractory to pro-inflammatory stimuli. Thus, preventing cholesterol efflux in TAM could represent a novel therapeutic strategy to block pro-tumor functions and restore anti-tumor immunity.
2019-02-05 | GSE126080 | GEO
Project description:Background: We have applied an integrative approach, including classical genomic, microarray, and refined computational systems biology to study the regulatory pathways that involve DNA damage associated with typical drug preparations of Tamoxifen (TAM). We compared the effects of newly formulated Nano-emulsions of TAM (NanoTAM or N-TAM) on cultured HTB-20 cells to those of liquid preparations of TAM. Phenotypic screening was used to identify changes induced. Implicated regulatory pathways were systematically investigated by chromatin immunoprecipitation (ChIP) and DNA microarray analyses to identify alterations in protein-DNA interactions as well as genome-wide expression patterns. While liquid solutions of clinically used TAM can have a Z-score average of thousands of nm, after encapsulation and application of high pressure particle size was ~41 nm. ChIP-chip technology was used to classify promoter regions for target genes bound by E2F4 in human primary HTB-20 cells upon treatment with TAM or N-TAM. Specific drug effects were defined by comparing results obtained for Control/Control (CC) Control/Nano (CN), TAM (Drug)/Control (TC), and N-TAM (Drug)/Nano (TN). Functional effects noted included changes in apoptosis, cell proliferation, RNA processing, DNA damage, repair and replication, lipid and protein metabolism, transport, and transcriptional regulators. Cells treated with clinical TAM only expressed the ataxia telangiectasia mutated protein ATM as well as several histone proteins important for DNA damage sensing and activation of repair proteins, while N-TAM did not illicit this response.. In contrast N-TAM could not only enter the cells it could cross the inner mitochondrial membrane, induced more apoptosis and affecting mitochondrial DNA.
2021-06-25 | GSE178880 | GEO