Targeting MAPK14 by lobeline upregulates Slurp1-mediated inhibition of alternative activation of TAM and retards colorectal cancer growth
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ABSTRACT:
PROVIDER: PRJNA1040812 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26841267_1.fastq.gz | Fastqsanger.gz | |||
| SRR26841267_2.fastq.gz | Fastqsanger.gz | |||
| SRR26841268_1.fastq.gz | Fastqsanger.gz | |||
| SRR26841268_2.fastq.gz | Fastqsanger.gz |
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Project description:Colorectal cancer often produces an immunosuppressive microenvironment, which prevents them from responding to immunotherapy. Effective treatment options have not been found yet. Here, based on the observation that Lobeline, an alkaloid from the herbal medicine Lobelia Chinensis, inhibited tumor in MC38 colon cancer xenograft mouse model. We performed single-cell transcriptome sequencing analysis of Lobeline and PBS-treated tumors in mice, and found that Lobeline promoted TAM polarization towards M1-like while inhibited its polarization towards M2-like. In addition, Lobeline upregulated the mRNA level of secreted Ly-6/UPAR-related protein 1 (Slurp1) in cancer cells. The inhibitory effect of Lobeline on tumor load and regulation of TAM polarization disappeard in Slurp1-/- mice or WT mice injected with Slurp1 knockdown adenovirus, suggesting that Slurp1 mediates the process of Lobeline regulates TAM polarization and inhibits tumor progression. Through target responsive accessibility profiling (TRAP), isothermal titration calorimetry (ITC) and microcalorimetric mobility shift assay (MST), we demonstrated that MAPK14 was the target protein of Lobeline. At the mechanistic level, upon binding to MAPK14 in colon cancer cells, Lobeline prevented the nuclear translocation of MAPK14, which decreases the level of phosphorylated p53. Subsequently, the negative transcriptional regulation of Slurp1 by p53 was inhibited, that facilitated the transcription and secretion of Slurp1. Furthermore, the combination of Lobeline and PD-1 antibody showed stronger anti-tumor effect. Thus, these findings suggested that the Lobeline-mediated anti-tumor immune activation might be a promising therapeutic strategy for colorectal cancer.
2025-02-13 | GSE247841 | GEO
Project description:Colorectal cancer (CRC) usually creates an immunosuppressive microenvironment, thereby hindering immunotherapy response. Effective treatment options remain elusive. Using scRNA-seq analysis in a tumor-bearing murine model, it is found that lobeline, an alkaloid from the herbal medicine lobelia, promotes polarization of tumor-associated macrophages (TAMs) toward M1-like TAMs while inhibiting their polarization toward M2-like TAMs. Additionally, lobeline upregulates mRNA expression of secreted Ly-6/UPAR-related protein 1 (Slurp1) in cancer cells. The inhibitory effects of lobeline on tumor load and TAM polarization are almost completely eliminated when Slurp1-deficient MC38 cells are subcutaneously injected into mice, suggesting that lobeline exerts an antitumor effect in a Slurp1-dependent manner. Furthermore, using target-responsive accessibility profiling, MAPK14 is identified as the direct target protein of lobeline. Mechanistically, upon binding to MAPK14 in colon cancer cells, lobeline prevents nuclear translocation of MAPK14, resulting in decreased levels of phosphorylated p53. Consequently, negative transcriptional regulation of SLURP1 by p53 is suppressed, leading to enhanced transcription and secretion of SLURP1. Finally, combination therapy using lobeline and anti-PD1 exhibits stronger antitumor effects. Taken together, these findings suggest that remodeling the immunosuppressive microenvironment using small-molecule lobeline may represent a promising therapeutic strategy for CRC.
| S-EPMC11904982 | biostudies-literature
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: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: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:Gene expression was analyzed in TAM from mice injected with ID8 ovarian cancer cells intraperitoneally in ABC a1/g1 fl/fl-LysM-Cre mice. 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 | GSE126079 | GEO
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: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: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
Project description:The tumor microenvironment modifies the malignancy of tumors. In solid tumors this environment is populated by many macrophages (tumor-associated macrophages; TAMs) that in genetic studies that depleted these cells from mouse models of breast cancer were shown to promote tumor progression to malignancy and increase metastatic potential. Mechanistic studies showed that these effects are through the stimulation of tumor cell migration, invasion, intravasation as well as an enhancement of angiogenesis. Using an in vivo invasion assay it was demonstrated that invasive carcinoma cells are a unique sub-population of tumor cells whose invasion and chemotaxis is dependent upon the co-migration of TAMs with obligate reciprocal signaling through an EGF/CSF-1 paracrine loop. In this study these invasion-promoting macrophages were isolated and subjected to analysis of their transcriptome in comparison to TAMs isolated indiscriminately to function using established macrophage markers by flow cytometry. Five biological replicates for each population (Invasive and General TAM) were used.
2010-05-16 | E-GEOD-18295 | biostudies-arrayexpress