DNA methylation landscape and transcriptome of tumor-associated macrophages reveals pathways, transcription factors, and prognostic value relevant for breast cancer patients [RNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE195857 | GEO | 2022/11/04
REPOSITORIES: GEO
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Project description:DNA methylation profiling of tumor-associated macrophages (TAMs), mammary gland macrophages (MGMs), bone marrow-derived monocytes from healthy (BMDM-Hs), and tumor-bearing mice (BMDM-Ts).
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Project description:Hematopoietic stem/progenitor cells (HS/PCs) were transduced with lentiviral vectors overexpressing OFP and either miR-511-3p or a control, mutated miRNA sequence (miR-511-3p-mut). The transduced HS/PCs were then transplanted in recipient C57BL/6 mice. Tumors (Lewis lung carcinomas, LLC) were injected s.c. 4 weeks after HS/PC transplant. Lentiviral vector-transduced (OFP+), tumor-associated macrophages (TAMs) were isolated 4 weeks after LLC injection by fluorescence-activated cell sorting. Gene expression profiles of TAMs overexpressing either miR-511-3p or miR-511-3p-mut were obtained from 3 independent biological samples/each. Gene expression profiles of miRNA-overexpressing TAMs were then compared with the gene expression profiles of wild-type TAMs isolated from LLCs grown in nontransplanted C57BL/6 mice; the latter TAMs were subfractioned into MRC1+CD11c(low) or CD11c+MRC1(low) subsets before RNA isolation and analysis. Comparison of gene expression profiles of TAMs revealed that miR-511-3p overexpression tunes down the expression of multiple genes that are classically upregulated in protumoral MRC1+CD11c(low) TAMs. TAMs were isolated from Lewis lung carcinomas grown s.c. in C57BL/6 mice.
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Project description:To better understand the impact of integrin beta3 signaling in myeloid cells on the tumor microenvironment, we compared the gene expression profiles of FACS isolated GFP+ PyMT-BO1 MFP tumor cells and also M2 TAMs (CD11b+Gr1-F4/80+CD206+) from tumor tissue of WT mice and b3ÎÎÎ mice. PyMT-BO1-GFP-Luc tumor cells (100,000) were injected into mammary fat pad (MFP) tissue from WT and b3KOM mice. PyMT-BO1-GFP-Luc cells and CD206hi tumor-associated macrophages (TAMs) were FACS-sorted from day 10 MFP tumor tissue. FACS-sorted cells directly used for RNA extraction and hybridization on Affymetrix microarrays.
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Project description:Hematopoietic stem/progenitor cells (HS/PCs) were transduced with lentiviral vectors overexpressing OFP and either miR-511-3p or a control, mutated miRNA sequence (miR-511-3p-mut). The transduced HS/PCs were then transplanted in recipient C57BL/6 mice. Tumors (Lewis lung carcinomas, LLC) were injected s.c. 4 weeks after HS/PC transplant. Lentiviral vector-transduced (OFP+), tumor-associated macrophages (TAMs) were isolated 4 weeks after LLC injection by fluorescence-activated cell sorting. Gene expression profiles of TAMs overexpressing either miR-511-3p or miR-511-3p-mut were obtained from 3 independent biological samples/each. Gene expression profiles of miRNA-overexpressing TAMs were then compared with the gene expression profiles of wild-type TAMs isolated from LLCs grown in nontransplanted C57BL/6 mice; the latter TAMs were subfractioned into MRC1+CD11c(low) or CD11c+MRC1(low) subsets before RNA isolation and analysis. Comparison of gene expression profiles of TAMs revealed that miR-511-3p overexpression tunes down the expression of multiple genes that are classically upregulated in protumoral MRC1+CD11c(low) TAMs.
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Project description:Tumour-associated macrophages (TAMs), as one of the most abundant and phagocytic tumour-infiltrating immune cells, play a pivotal role in tumour antigen clearance and immune suppression. M2-like TAMs present a heightened lysosomal acidity and protease activity, which limits the function of antigen cross-presentation. How to selectively reprogram the antigen-destroying TAMs to a restorative phenotype for efficient anti-tumour immunity is challenging. Here, we report a pH-gated nanoadjuvant (PGN) that selectively targets the lysosomes of M2-like TAMs in tumours rather than the corresponding organelles from macrophages in healthy tissues. Enabled by the PGN nanotechnology, M2-like TAMs are specifically switched to M1-like phenotypes with tuned-down lysosomal function featured by attenuated lysosomal acidity and cathepsin activity for improved antigen cross-presentation, thus provoking adaptive immune response and sustained tumour regression. Our findings provide new insights into how to specifically regulate lysosomal function of TAMs for efficient cancer immunotherapy.
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Project description:Tumor-associated macrophages (TAMs) are known to be involved in progression, angiogenesis and motility of various cancers. We have previously reported the association between increased number of infiltrating TAMs with tumor progression and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To study roles of TAMs in ESCC, we first exposed peripheral blood monocytes (PBMo) derived macrophages from healthy volunteers to conditioned media of TE series human ESCC cell line (TECM) and confirmed the induction of expression of M2 macrophage marker, CD204, and protumorigenic factors, interleukin (IL)-10, VEGFA and MMPs. Next, we compared gene expression profile between PBMo-derived macrophages and PBMo-derived macrophages stimulated with TECM by cDNA microarray. Based on the result, we focused on growth differentiation factor 15 (GDF15) among highly expressed genes including IL-6, IL-8 and CXCL1. Immunohistochemical study on 70 cases of surgically resected ESCCs revealed that GDF15 was detected not only in macrophages but also in cancer cells. High expression of GDF15 in ESCCs was significantly correlated with more malignant phenotypes including lymph and blood vessel invasion, lymph node metastasis as well as clinical stages. Patients with high expression of GDF15 showed poor disease-free survival (p = 0.011) and overall survival (p = 0.041). Furthermore, we found that recombinant human GDF15 promote cell proliferation and phosphorylation of both Akt and Erk1/2 in ESCC cell lines in vitro. These results indicate that GDF15 is secreted by both TAMs and cancer cells in tumor microenvironment and is associated with aberrant growth and poor prognosis of human ESCC. We exposed PBMo-derived macrophages from healthy volunteers to TECM and observed their acquisition of TAM-like characters in this study. We further investigated specific cancer-associated gene expression profile in TECM induced TAM-like macrophages by cDNA microarray analysis.
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2012-03-31 | E-GEOD-18804 | biostudies-arrayexpress
Project description:Tumor-associated macrophages (TAMs) represent alternatively activated (M2) macrophages that support tumor growth. Previously, we have described a special LYVE-1(+) M2 TAM subset in vitro and in vivo; gene profiling of this TAM subset identified MS4A8A as a novel TAM molecule expressed in vivo by TAM in mammary carcinoma and malignant melanoma. In vitro, Ms4a8a mRNA and MS4A8A protein expression was strongly induced in bone marrow-derived macrophages (BMDMs) by combining M2 mediators (IL-4, glucocorticoids) and tumor-conditioned media (TCM). Admixture of MS4A8A(+) TCM/IL-4/GC-treated BMDM significantly enhanced the tumor growth rate of subcutaneously transplanted TS/A mammary carcinomas. Upon forced overexpression of MS4A8A, Raw 264.7 macrophage-like cells displayed a special gene signature. Admixture of these MS4A8A(+) Raw 264.7 cells also significantly enhanced the tumor growth rate of subcutaneously transplanted mammary carcinomas. To identify the signaling pathways involved in synergistic induction of MS4A8A, the major signaling cascades with known functions in TAM were analyzed. Although inhibitors of NF-κB activation and of the MAPK JNK and ERK did not show relevant effects, the p38α/β MAPK inhibitor SB203580 strongly and highly significantly (p > 0.001) inhibited MS4A8A expression on mRNA and protein level. In addition, MS4A8A expression was restricted in M2 BMDM from mice with defective GC receptor (GR) dimerization indicating that classical GR gene regulation is mandatory for MS4A8A induction. In conclusion, expression of MS4A8A within the complex signal integration during macrophage immune responses may act to fine tune gene regulation. Furthermore, MS4A8A(+) TAM may serve as a novel cellular target for selective cancer therapy.
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Project description:Targeting the reprogramming and phagocytic capacities of tumor-associated macrophages (TAMs) has emerged as a therapeutic opportunity for cancer treatment. Here, we demonstrate that leukemic cell phagocytosis triggers the proinflammatory activation of TAMs as demonstrated by the upregulation and dowregulation of, respectively, proinflammatory and anti-inflammatory genes in phagocytic macrophages (Phago+) with respect to non-phagocytic macrophages (Phago-).
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Project description:Tumor-associated macrophages (TAMs) represent alternatively activated (M2) macrophages that support tumor growth. Previously, we have described a special LYVE-1(+) M2 TAM subset in vitro and in vivo; gene profiling of this TAM subset identified MS4A8A as a novel TAM molecule expressed in vivo by TAM in mammary carcinoma and malignant melanoma. In vitro, Ms4a8a mRNA and MS4A8A protein expression was strongly induced in bone marrow-derived macrophages (BMDMs) by combining M2 mediators (IL-4, glucocorticoids) and tumor-conditioned media (TCM). Admixture of MS4A8A(+) TCM/IL-4/GC-treated BMDM significantly enhanced the tumor growth rate of subcutaneously transplanted TS/A mammary carcinomas. Upon forced overexpression of MS4A8A, Raw 264.7 macrophage-like cells displayed a special gene signature. Admixture of these MS4A8A(+) Raw 264.7 cells also significantly enhanced the tumor growth rate of subcutaneously transplanted mammary carcinomas. To identify the signaling pathways involved in synergistic induction of MS4A8A, the major signaling cascades with known functions in TAM were analyzed. Although inhibitors of NF-M-NM-:B activation and of the MAPK JNK and ERK did not show relevant effects, the p38M-NM-1/M-NM-2 MAPK inhibitor SB203580 strongly and highly significantly (p > 0.001) inhibited MS4A8A expression on mRNA and protein level. In addition, MS4A8A expression was restricted in M2 BMDM from mice with defective GC receptor (GR) dimerization indicating that classical GR gene regulation is mandatory for MS4A8A induction. In conclusion, expression of MS4A8A within the complex signal integration during macrophage immune responses may act to fine tune gene regulation. Furthermore, MS4A8A(+) TAM may serve as a novel cellular target for selective cancer therapy. A recombinant Ms4a8a cDNA was amplified by PCR (primer: Ms4a8a-SpeI-fw 5M-bM-^@M-^YATCGAATTCACTAGTAGCAAAGAGTTGGGAACCGGAGCAAGA3M-bM-^@M-^Y and Ms4a8a-NotI-rv: 5M-bM-^@M-^YATATGCGGCCGCTAGAGCATCTTTAT3M-bM-^@M-^Y) from Ms4a8a cDNA RZPDp981B0530D (IMAGE ID 905005), purified on agarose gel and subcloned after digestion with SpeI and NotI restriction enzymes into the expression vector pEF6/V5-His Topo (Invitrogen) according to standard molecular biology protocols. After confirming sequence identity, we transfected RAW264.7 cells with Ms4a8a vector DNA using Lipofectamine 2000 (Invitrogen) transfection reagent. Transfectants were selected by resistance to blasticidin (Invitrogen). Raw264.7Ms4a8a clone K8 with recombinant Ms4a4a expression were propagated. As a negative control, a vector-transfected RAW264.7mock (clone K3) was selected under parallel culture conditions.
2012-05-22 | E-GEOD-38171 | biostudies-arrayexpress