MiR-100 maintains phenotype of tumor associated macrophages by targeting mTOR to promote tumor metastasis via Stat5a/IL-1ra pathway in mouse breast cancer
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PROVIDER: PRJNA474505 | ENA |
REPOSITORIES: ENA
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Project description:Tumor-associated macrophages (TAMs)，the main part of immune cells in tumor microenvironment (TME)，play a potent role in promoting tumorigenesis through mechanisms such as stimulating angiogenesis, enhancing tumor migration and suppressing antitumor immunity. MicroRNAs (miRNAs) are considered as crucial regulators in multiple biological processes. The relationship between miRNAs and macrophages function has been extensively reported, but the roles that miRNAs play in regulating TAMs phenotype remains unclear. In this study, we screened highly-expressed microRNAs in TAMs, and first identified that miR-100 represented a TAMs-high expression pattern and maintained TAMs phenotype by targeting mTOR signaling pathway. Moreover, miR-100 expression level in TAMs was positively related to IL-1ra secretion, a traditional immune-suppressive cytokine, which was determined to promote tumor cells stemness via stimulating Hedgehog pathway. Mechanism study suggested that mTOR/Stat5a pathway was involved in IL-1ra transcriptional regulation process mediated by miR-100. More importantly, tumor metastasis and invasion capacity were significantly decreased in a 4T1 mouse breast cancer model injected intratumorally with miR-100 antagomir, and combination therapy with cisplatin showed much better benefit. In this study, we confirmed that highly expressed miR-100 maintains the phenotype of TAMs and promotes tumor metastasis via enhancing IL-1ra secretion. Interfering miR-100 expression of TAMs in mouse breast cancer model could inhibit TAMs pro-tumor function and reduce tumor metastasis, which suggested that miR-100 could serve as a potential therapy target to remodel tumor microenvironment in breast cancer.
2019-06-03 | GSE115295 | GEO
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Project description:Tumor-associated microglia and macrophages (TAM) are the most numerous non-neoplastic populations in the tumor microenvironment of glioblastoma (GBM), the most common malignant brain tumor in adulthood. The mTOR pathway, an important regulator of cell survival and proliferation, is known to be upregulated in GBM, but little is known about a potential role of this pathway in TAM. Here, we show that GBM-initiating cells (GIC) induce mTOR signalling in TAM-Microglia (TAM-MG) but not TAM-Macrophages (TAM-BMDM) in in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-ĸB activity promotes an immunosuppressed phenotype in TAM-MG which hinders effector T cell proliferation and immune reactivity, thereby contributing to tumor immune evasion and promoting tumor growth in a mouse model. The translational value of these results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model whereby IPSC-derived microglia-like cells are conditioned by syngeneic patient-derived GIC. These results raise the possibility that tumor cells might not be the primary target of mTOR inhibition, and TAM-MG should be considered instead.
2020-07-21 | GSE147329 | GEO
Project description:Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. However, the use of mTOR inhibitors as single agents have shown limited clinical efficacy in relation with drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we evaluated the antitumor activity of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in primary MCL cells. We found that dual PI3K/mTOR inhibitor modulated angiogenesis, tumor invasiveness and cytokine signaling compared to a mTOR inhibitor and a pan-PI3K inhibitor in MCL. We used microarrays to compare the effect of these three compounds in MCL and identified distinct classes of down-regulated genes modulated by each compound. Global RNA expression in primary cells from two MCL patients treated with a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor for 8 hours
2013-12-14 | E-GEOD-53309 | biostudies-arrayexpress
Project description:The mammalian target of rapamycin (mTOR) is a central regulator of cell proliferation. Inhibitors of mTOR are being evaluated as anti-tumor agents. Given the emerging role of microRNAs (miRNAs) in tumorgenesis we hypothesized that miRNAs could play important roles in the response of tumors to mTOR inhibitors. Rapamycin resistant myogenic cells developed by long-term rapamycin treatment showed extensive reprogramming of miRNAs expression, characterized by up-regulation of the mir-17~92 and related clusters and down-regulation of tumor-suppressor miRNAs. Antagonists of oncogenic miRNA families and mimics of tumor suppressor miRNAs (let-7) restored rapamycin sensitivity in resistant tumor cells. This study identified miRNAs as new downstream components of the mTOR-signaling pathway, which may determine the response of tumors to mTOR inhibitors. Total RNA was extracted from rapamycin sensitive (RS) cells (BC3H1, mouse brain tumor cell line with myogenic properties, ATCC) cultured in Dulbecco’s modified essential medium (DMEM) media supplemented with 20% fetal bovine serum (FBS), penicillin (100 U/ml) and streptomycin (100 mg/ml). Rapamycin resistant cells (RR1) were developed by culturing BC3H1 cells in the presence of 1 uM rapamycin for 6 months. Three samples in quadruplicate 1)RS cells treated with DMSO for 24 h(BC3H1, reference), 2) RS cells treated for 24 h with 100 nM rapamycin (BC3H1+R), 3) RR1 cells consantly treated with 1uM Rapamycion (RR1+R). For each experiment, 1 μM of total RNA was labeled with Hy3TM dye and a reference RNA pool (consisting of a mixture of equal amounts of total RNA from BC3H1, BC3H1+R and RR1+R cells) was labeled with Hy5TM dye using the miRCURYTM Labeling Kit. The samples were hybridized to Exiqon miRCURYTM LNA Arrays (V10.0).
2013-02-08 | E-GEOD-19916 | biostudies-arrayexpress
Project description:The TSC/mTOR (tuberous sclerosis complex/mammalian target of rapamycin) pathway has a central role in cell growth and is involved in human tumorigenesis. Here, we demonstrate an unexpected role of TSC2 and mTOR in regulating key inflammatory cytokines in monocytes, macrophages, and dendritic cells after bacterial stimulation. mTOR deficiency promoted IL-12/IL-23 and blocked IL-10 production via the transcription factor NF-kB. Conversely, loss of TSC2, a key negative regulator of mTOR, led to reduced NF-kB activity, limited IL-12 but enhanced IL-10 production. Transcriptional profiling demonstrated that mTOR additionally regulated many mediators important for inflammation and immunoregulation including PD-L1, CCR5, CCL22, and MCP-1. mTOR inhibition in vivo rescued susceptible mice from a lethal Listeria monocytogenes infection by modulating IL-12/IL-10 production. These data identify the TSC2/mTOR pathway as a novel pathway in innate immune responses by controlling NF-kB with profound clinical implications for infectious diseases, cancer, or transplantation. Keywords: inflammatory response of monocytes to LPS and rapamycin 107 CD14+ monocytes from four different donors were stimulated with 100 ng/ml LPS with or without 100 nM rapamycin for 4 hours. Cells were harvested, washed and pelleted and frozen at â80° C. Sample preparation and hybridization to a PIQORTM Immunology Microarray Human Antisense (quadrupled cDNA fragments for 1070 genes) was performed at the Miltenyi Microarray Service Unit. In brief, RNA was extracted with the TRIzol method (Sigma-Aldrich) and 1mg of total RNA was linear amplified by T7 polymerase. Total RNA from the LPS treated cells were Cy3 labeled, LPS and rapamycin treated cells were Cy5 labeled; both samples of a donor were hybridized on a single microarray. Only genes with signal intensities >2-fold above average background in one of the two channels were regarded as expressed.
2010-05-19 | E-GEOD-6002 | biostudies-arrayexpress
Project description:Lck-MyrAkt2 mice develop spontaneous thymic lymphomas at approximately 100-200 days of age, driven in part by a consitutatively-active AKT (due to myristoylation). mTOR Knock Down mice were crossed with Lck-MyrAkt postive mice to model the affects of decreasing mTOR activity on tumors with an activated PI3K/AKT/MTOR pathway. Lck-Akt/mTOR KD mice had prolonged survival compared to the Lck-Akt/mTOR WT mice. We used microarrays to compare the transcriptome in thymic lymphomas between Lck-Akt positive, mTOR WT and Lck-Akt positive, mTOR KD mice. Four thymic lymphomas from Lck-Akt/mTOR WT mice were compared to three thymic lymphomas from Lck-Akt/mTOR KD mice.
2015-09-15 | E-MTAB-3242 | biostudies-arrayexpress