ChREBP-mediated choline deprivation and chemokine secretion shape TAMs to promote immune evasion
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ABSTRACT:
PROVIDER: PRJNA1166132 | ENA |
REPOSITORIES: ENA
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Project description:Tumor metabolic reprogramming has been recognized as a critical determinant in tumor development and cancer immunotherapy. Aberrant choline metabolism is emerging as a defining hallmark of cancer. However, its impact on antitumor immunity remains largely unclear. Carbohydrate responsive element binding protein (ChREBP)-mediated choline deprivation impels tumor-associated macrophages (TAMs) reprogramming and maintains an immunosuppressive tumor microenvironment (TME). Mechanistically, ChREBP interacts with SP1 to increase the expression of immunosuppressive chemokines CCL2 and CXCL1, as well as choline transporter SLC44A1. As such, high expression of CCL2 and CXCL1 expression promotes recruitment of TAMs and MDSCs in the TME. Tumor cells with high SLC44A1 expression compete consuming choline with M1-like TAMs, inhibiting cGAS-STING signaling and promoting the polarization of M1 to M2 macrophages. Clinically, ChREBP-SP1-choline metabolism axis expression is associated with poor clinical outcome in CRC. Inhibiting ChREBP reduces M2-like TAMs and MDSCs to enhance anti-tumor immunity, suggesting ChREBP as a potential immunotherapy target in cancer.
2025-01-01 | GSE278229 | GEO
Project description:This project investigated proline hydroxylation of ChREBP. Proline hydroxylation was investigated in flag-IP enriched protein extracts from ChREBP-flag overexpressing HEK293 cells (A) and in ChREBP-IP enriched mouse liver protein (male, C57BL6/J) (B).
2020-10-19 | PXD019137 | Pride
Project description:Choline and methionine/choline deficient diets are widely used to generate severe rodent hepatic steatosis and steatohepatitis in an attempt to reflect stages of human non-alcoholic fatty liver disease (NAFLD). The underlying mechanism of hepatic injury in these models, and how this reflects human disease remains incompletely understood. We used detailed transcriptional analysis to interrogate the molecular mechanisms of this intervention and its similarity to human disease. Adult C57Bl/6J mice were maintained on control, choline deficient (CDD) or methionine/choline deficient (MCDD) diets for 4 weeks. Isolated liver RNA was used for transcriptional profiling by micro array analysis.
2016-06-01 | E-MTAB-3943 | biostudies-arrayexpress
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.
2012-04-01 | E-GEOD-34903 | biostudies-arrayexpress
Project description:Epidemiologic and animal studies implicate overconsumption of fructose in the development of non-alcoholic fatty liver disease, but the molecular mechanisms underlying fructose-induced chronic liver diseases remains largely unknown. We present evidence supporting the essential function of the lipogenic transcription factor ChREBP in mediating adaptation response to fructose and protecting against fructose-induced hepatotoxicity. High-fructose diet (HFrD) activates hepatic lipogenesis via a ChREBP-dependent manner in wildtype mice, while inducing steatohepatitis in Chrebp-KO mice. In Chrebp-KO mouse livers, HFrD reduces levels of molecular chaperones and activates the CHOP-dependent unfolded protein response, whereas administration of chemical chaperone or Chop shRNA rescues liver injury. Gene expression profiling revealed elevated expression of cholesterol biosynthesis genes in Chrebp-KO livers after HFrD, in parallel with increased abundance of nuclear SREBP2. genes expression were compared between livers of wildtype mice fed 70%-fructose-diet v.s. regular chow, and between livers of Chrebp-/- mice v.s. wildtype mice fed 70%-fructose-diet.
2017-03-21 | GSE96820 | GEO
Project description:Tumor-associated macrophages (TAMs) are a major component of the leukocyte and a heterogenous population in tumors. Recent reports have increasingly suggested that manipulating the function of TAMs may serve as a promising therapeutic strategy against advanced tumors. Our present work indicates that CSF-1R+ TAMs are abundantly found in a significant proportion of COAD specimens. Therefore，to determine the role of the CSF-1Rhigh TAMs in COAD, we sorted the CSF-1Rhigh TAMs and the CSF-1R low TAMs from the colon adenocarcinomas for Smart-seq2. We found that CSF-1Rhigh TAM infiltration involved in multiple tumor immune signaling pathways. CSF-1Rhigh TAMs mostly exhibited a immunosuppressive phenotypes, and were associated with enhanced levels of Treg cells. CSF-1R high TAMs promotes COAD progression by modulating tumor immunity environment
2022-03-31 | GSE193814 | GEO
Project description:Active immunotherapy is a promising strategy for anti-angiogenic cancer therapy. Recently, we have reported that a vaccine using human umbilical vein endothelial cells (HUVECs) induced specific anti-endothelial immune responses in the most of immunized patients, and resulted in tumor regression in some patients with recurrent malignant brain tumors, whereas not in colorectal cancer patients. In this study, we hypothesized that non-hypoxic perivascular tumor associated macrophages (TAMs) in colorectal cancer, but not in glioblastoma, might negatively alter the therapeutic efficacy of anti-angiogenic active immunotherapy. To test this hypothesis, we examined global gene expression profiles of non-hypoxic macrophages stimulated in vitro by soluble factors released from tumor cells of human glioblastoma U-87MG (‘brain TAMs’) or colorectal adenocarcinoma HT-29 (‘colon TAMs’). Murine non-hypoxic TAMs were induced in vitro by incubation with soluble factors released from human cancer cell lines U-87MG ('brain TAMs') or HT-29 ('colon TAMs'), for RNA extraction and subsequent hybridization on Affymetrix microarrays. To evaluate homogeneous macrophage populations at different tumour developmental stages, RNA aliquots of control macrophages and TAMs obtained at five different time-points, i.e. 8h, 16h, 24h, 32h and 40h, were pooled and used for screening of differentially expressed genes. The experiments for TAMs as well as for control unstimulated macrophages were performed in triplicates.
2012-03-31 | E-GEOD-18804 | biostudies-arrayexpress
Project description:By analogy to the c-Myc (Myc)/Max family of transcription factors, there also exists a “parallel” network of structurally and functionally related bHLH-ZIP proteins with certain Myc-like functions. Two closely related “Myc-like” paralogs termed Mondo A and MondoB/ChREBP (ChREBP) positively regulate gene expression in heterodimeric association with the Max-like factor Mlx. Myc is necessary to support liver cancer cell growth but not for normal hepatocyte proliferation. Here, we investigated the role for ChREBP and its relationship to Myc in these processes. Unlike Myc, ChREBP loss conferred a marked proliferative disadvantage to normal hepatocytes as did the loss of both ChREBP and Myc. In addition, hepatoblastomas (HBs) originating in myc-/-, chrebp-/- or myc-/-/chrebp-/- backgrounds grew significantly more slowly. Metabolic studies performed on livers and HBs arising in all three backgrounds showed marked differences in oxidative phosphorylation, fatty acid -oxidation (FAO) and the activity of pyruvate dehydrogenase. RNAseq of livers and HBs indicated seven distinct forms of target transcript regulation. Gene ontology analysis indicated that many transcripts de-regulated in the chrebp-/- background encode enzymes functioning in glycolysis, the TCA cycle and - and-FAO whereas those in myc-/- background encode enzymes for glycolysis, glutaminolysis and sterol biosynthesis. Transcript de-regulation in the double knockout group was similar but also included those involved in peroxisomal - and -FAO. Finally, we identified cooperative positive regulation by Myc and ChREBP of virtually all ribosomal protein genes. Our findings define the global proliferative, metabolic and transcriptional roles for the more general “Extended Myc Network” under both normal and neoplastic conditions.
2018-08-09 | GSE114634 | GEO
Project description:Intramuscular fat (IMF) content is one of the key factors affecting meat quality. Carbohydrate response element binding protein (ChREBP) can promote glucose metabolism and fat synthesis by activating the expression of glycolysis and lipogenesis-related genes, but its function and regulatory mechanism in IMF are still unclear. This study evaluated the correlation between TG content and ChREBP expression level in muscles of different species to reveal the relationship between ChREBP and IMF. RNA-seq analysis showed that overexpressing ChREBP in C2C12 cells can significantly up-regulate fatty acid synthesis pathways, while significantly down-regulate the expression levels of muscle development pathways and related genes. In vivo, we found that overexpression of ChREBP or activation by fructose significantly increased the triglyceride content of the tibialis anterior muscle (TA) and the IMF content of yellow feather chicken leg and breast muscle in mice. And lipidomics data also found that feeding fructose can change the lipid composition of yellow feather broiler breast muscle and improve the flavor substances. This study demonstrated that ChREBP is a key gene regulating IMF deposition, providing a new target for genetic selection and nutritional regulation of IMF content.
2024-08-08 | GSE228899 | GEO
Project description:Glucose is an important regulator of pancreatic β-cell function. In addition to the acute stimulation of insulin secretion, glucose stimulates long-term adaptive changes in gene expression that can either promote or antagonize the proliferative potential and function of β-cells. The glucose-sensing transcription factor carbohydrate response element binding protein (ChREBP) has been shown to promote both β-cell proliferation and dysfunction; however, the molecular mechanisms underlying these pleiotropic effects of ChREBP and glucose are not well understood. Here, we have generated time-resolved profiles of enhancer and transcriptional activity in response to glucose in the INS-1E pancreatic β-cell line. Our data outline a biphasic response with a first wave during which metabolic genes are activated, and a second wave where cell cycle genes are induced and β-cell identity genes are repressed. We show that ChREBP directly activates first wave genes, whereas repression and activation of second wave genes by ChREBP is indirect. By integrating motif enrichment within late-regulated enhancers with expression profiles of the associated transcription factors, we identify multiple putative regulators of the second wave, including RAR-related orphan receptor (ROR) γ, which we demonstrate is a novel direct ChREBP target gene. Importantly, we show that RORγ activity is necessary for full glucose-induced proliferation of both INS-1E and primary rat β-cells. Genome-wide assesment of the transcriptional response to glucose in INS-1E β-cells using RNA- ChIP- and DNase-seq
2016-09-06 | E-GEOD-81628 | biostudies-arrayexpress