Targeting the Mapk13-Tcf1-Slc7a5 Axis via One-Carbon Metabolic Regulation to Prevent Chronic Allograft Vasculopathy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE314157 | GEO | 2026/04/08
REPOSITORIES: GEO
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Project description:Targeting the Mapk13-Tcf1-Slc7a5 Axis via One-Carbon Metabolic Regulation to Prevent Chronic Allograft Vasculopathy
| PRJNA1390187 | ENA
Project description:The effects of loss of the large neutral amino acid transporter Slc7a5 (aka Lat1) on mouse embryonic development were investigated. Slc7a5 fl/fl mice harbouring two copies of the Slc7a5 targeted allele (exon 1 of Slc7a5 flanked with two loxP sites), were crossed with a mouse line ubiquitously expressing cre recombinase under the Bal1 promoter (Bal1-cre) to obtain a global Slc7a5 knockout mouse (Poncet et al. 2014 PLoS One 9: e89547). Heterozygous Slc7a5+/- C57Bl/6 mice were viable and fertile and were bred free of Bal1-cre in subsequent generations. Slc7a5 -/- embryos were obtained by inter-crossing heterozygotes and a phenotype was apparent by E9.5. To identify the first cellular processes affected by Slc7a5 loss RNAseq was carried out to compare transcriptomes of null and wildtype E8.5 embryos.
2019-06-01 | E-MTAB-6336 | biostudies-arrayexpress
Project description:We report differences in gene expression between wildtype and Slc7a5 knockout CD4+ T cells obtained from mouse knee joints with antigen induced arthritis
2022-12-21 | GSE168750 | GEO
Project description:Background: Cardiac allograft vasculopathy (CAV), a diffuse thickening of the intima of the coronary arteries and microvasculature, is the leading cause of late graft failure and mortality after heart transplantation (HT). Diagnosis involves invasive coronary angiography, which carries substantial risk, and minimally-invasive approaches to CAV diagnosis are urgently needed. Using single-cell RNA-sequencing in peripheral blood mononuclear cells (PBMCs), we sought to identify cell-specific gene expression profiles in CAV. Methods: Whole blood was collected from 22 HT recipients with angiographically-confirmed CAV and 18 HT recipients without CAV. PBMCs were isolated and subjected to single-cell RNA-sequencing using a 10X Genomics microfluidic platform. Downstream analyses focused on differential expression of genes, cell compositional changes, and T cell receptor repertoire analyses. Results: Across 40 PBMC samples, we isolated 134,984 cells spanning 8 major clusters and 31 subclusters of cell types. Compositional analyses showed subtle, but significant increases in CD4+ T central memory cells, and CD14+ and CD16+ monocytes in high-grade CAV (CAV-2 and CAV-3) as compared to low-grade or absent CAV. After adjusting for age, gender, and prednisone use, 745 genes were differentially expressed in a cell-specific manner in high-grade CAV. Weighted gene co-expression network analyses showed enrichment for putative pathways involved in inflammation and angiogenesis. There were no significant differences in T cell clonality or diversity with increasing CAV severity. Conclusions: Unbiased whole transcriptomic analyses at single-cell resolution identify unique, cell-specific gene expression patterns in CAV, suggesting the potential utility of peripheral gene expression biomarkers in diagnosing CAV.
2024-12-21 | GSE271408 | GEO
Project description:T cell clonal expansion and differentiation are critically dependent on the transcription factor c-Myc (Myc). Herein we use quantitative mass-spectrometry to reveal how Myc controls antigen receptor driven cell growth and proteome restructuring in CD4+ and CD8+ T cells. Quantitative proteomics was performed on naive wild-type (WT) and 24 hr T cell receptor (TCR) activated Myc WT and Myc-deficient T cells. Analysis of copy numbers per cell of >7000 proteins provides new understanding of the selective role of Myc in controlling the protein machinery that shapes T cell fate. The data identify both Myc dependent and independent metabolic processes in immune activated T cells. We uncover that a primary function of Myc is to induce amino acid transporter expression. Quantitative proteomics of 24 hr TCR activated Slc7a5 WT and Slc7a5-deficient CD4 T cells reveals that loss of a single Myc-controlled amino transporter, Slc7a5, can effectively phenocopy the impact of Myc deletion. This study thus provides a comprehensive map of how Myc selectively shapes T cell phenotypes and reveals that Myc induction of amino acid transport is pivotal for subsequent bioenergetic and biosynthetic programs.
2020-02-25 | PXD016105 | Pride
Project description:Tumor antigen recognition and subsequent cytotoxic T lymphocyte (CTL) tumor infiltration are essential but alone are insufficient for an antitumor response. T cells nutrient uptake and metabolic reprogramming may dictate T cell differentiation and effector function to control CTL function in the tumor microenvironment. Slc7a5 is a system L transporter of large neutral amino acids and regulates T cell receptor (TCR)-mediated T cell activation during viral infection. Using tumor-specific CTL and antigen (Ag)-expressing tumor cell co-culture models, we determined that tumor-specific CTLs respond to tumor by increasing tryptophan uptake while responding to antigen alone without tumor cells by decreasing tryptophan uptake. ATAC-Seq analysis of the Ag-activated and tumor-activating CTLs revealed the transcriptional activation of a large set of transporters, including Slc7a5, a transporter for tryptophan. Slc7a5-specific inhibitor significantly decreased tryptophan uptake in the CTL-tumor co-culture while only tumor-specific CTLs and tumor are present in the microenvironment, indicating an essential role of Slc7a5 in transporting tryptophan in tumor-activated CTLs. We then generated mice with Slc7a5 deficiency only in T cells (Slc7a5.TKO). Transplanted breast tumor grew in a similar rate in WT and Slc7a5.TKO mice. However, Slc7a5.TKO mice formed significant more lung metastases than WTR mice. Further, transplanted melanoma tumor grew significantly faster in Slc7a5.TKO mice than in WT mice. Slc7a5.TKO mice show no significant difference in T cells as compared to WT mice. However, both CD4+ and CD8+ T cells diminished in tumors in the tumor-bearing mice, indicating an essential role of the Slc7a5-tryptophan metabolic pathway in T cell activation and expansion in the tumor microenvironment. scRNA-seq analysis determined that, unlike in the virus-infected host where MOTRC1 pathway is diminished, Slc7a5 deficiency leads to decreased AhR signaling and FasL expression in tumor-infiltrating T cells. Accordingly, FasL blockade increased lung metastases in breast tumor-bearing mice and increased tumor growth in melanoma tumor-bearing mice, indicating that Slc7a5 regulates the tryptophan-AhR metabolic pathway to regulate FasL expression in T cells to control tumor-infiltrating CTL effector function. Analysis of scRNA-seq dataset of human breast cancer patients revealed that FasL expression in T cells is correlated with SLC7A5 expression and patient response to immune checkpoint inhibitor immunotherapy. Furthermore, FasL is positively correlated with patient survival length in pooled datasets of 33 human cancers, and in human patients with breast cancer and melanoma in particular. Our findings determine that Slc7a5 controls tryptophan uptake in tumor-infiltrating CTLs to regulate the tryptophan-AhR metabolic pathway to regulate FasL expression to control CTL anti-tumor immune response.
2025-05-17 | GSE267840 | GEO
Project description:Tumor antigen recognition and subsequent cytotoxic T lymphocyte (CTL) tumor infiltration are essential but alone are insufficient for an antitumor response. T cells nutrient uptake and metabolic reprogramming may dictate T cell differentiation and effector function to control CTL function in the tumor microenvironment. Slc7a5 is a system L transporter of large neutral amino acids and regulates T cell receptor (TCR)-mediated T cell activation during viral infection. Using tumor-specific CTL and antigen (Ag)-expressing tumor cell co-culture models, we determined that tumor-specific CTLs respond to tumor by increasing tryptophan uptake while responding to antigen alone without tumor cells by decreasing tryptophan uptake. ATAC-Seq analysis of the Ag-activated and tumor-activating CTLs revealed the transcriptional activation of a large set of transporters, including Slc7a5, a transporter for tryptophan. Slc7a5-specific inhibitor significantly decreased tryptophan uptake in the CTL-tumor co-culture while only tumor-specific CTLs and tumor are present in the microenvironment, indicating an essential role of Slc7a5 in transporting tryptophan in tumor-activated CTLs. We then generated mice with Slc7a5 deficiency only in T cells (Slc7a5.TKO). Transplanted breast tumor grew in a similar rate in WT and Slc7a5.TKO mice. However, Slc7a5.TKO mice formed significant more lung metastases than WTR mice. Further, transplanted melanoma tumor grew significantly faster in Slc7a5.TKO mice than in WT mice. Slc7a5.TKO mice show no significant difference in T cells as compared to WT mice. However, both CD4+ and CD8+ T cells diminished in tumors in the tumor-bearing mice, indicating an essential role of the Slc7a5-tryptophan metabolic pathway in T cell activation and expansion in the tumor microenvironment. scRNA-seq analysis determined that, unlike in the virus-infected host where MOTRC1 pathway is diminished, Slc7a5 deficiency leads to decreased AhR signaling and FasL expression in tumor-infiltrating T cells. Accordingly, FasL blockade increased lung metastases in breast tumor-bearing mice and increased tumor growth in melanoma tumor-bearing mice, indicating that Slc7a5 regulates the tryptophan-AhR metabolic pathway to regulate FasL expression in T cells to control tumor-infiltrating CTL effector function. Analysis of scRNA-seq dataset of human breast cancer patients revealed that FasL expression in T cells is correlated with SLC7A5 expression and patient response to immune checkpoint inhibitor immunotherapy. Furthermore, FasL is positively correlated with patient survival length in pooled datasets of 33 human cancers, and in human patients with breast cancer and melanoma in particular. Our findings determine that Slc7a5 controls tryptophan uptake in tumor-infiltrating CTLs to regulate the tryptophan-AhR metabolic pathway to regulate FasL expression to control CTL anti-tumor immune response.
2025-05-17 | GSE267839 | GEO
Project description:Tumor antigen recognition and subsequent cytotoxic T lymphocyte (CTL) tumor infiltration are essential but alone are insufficient for an antitumor response. T cells nutrient uptake and metabolic reprogramming may dictate T cell differentiation and effector function to control CTL function in the tumor microenvironment. Slc7a5 is a system L transporter of large neutral amino acids and regulates T cell receptor (TCR)-mediated T cell activation during viral infection. Using tumor-specific CTL and antigen (Ag)-expressing tumor cell co-culture models, we determined that tumor-specific CTLs respond to tumor by increasing tryptophan uptake while responding to antigen alone without tumor cells by decreasing tryptophan uptake. ATAC-Seq analysis of the Ag-activated and tumor-activating CTLs revealed the transcriptional activation of a large set of transporters, including Slc7a5, a transporter for tryptophan. Slc7a5-specific inhibitor significantly decreased tryptophan uptake in the CTL-tumor co-culture while only tumor-specific CTLs and tumor are present in the microenvironment, indicating an essential role of Slc7a5 in transporting tryptophan in tumor-activated CTLs. We then generated mice with Slc7a5 deficiency only in T cells (Slc7a5.TKO). Transplanted breast tumor grew in a similar rate in WT and Slc7a5.TKO mice. However, Slc7a5.TKO mice formed significant more lung metastases than WTR mice. Further, transplanted melanoma tumor grew significantly faster in Slc7a5.TKO mice than in WT mice. Slc7a5.TKO mice show no significant difference in T cells as compared to WT mice. However, both CD4+ and CD8+ T cells diminished in tumors in the tumor-bearing mice, indicating an essential role of the Slc7a5-tryptophan metabolic pathway in T cell activation and expansion in the tumor microenvironment. scRNA-seq analysis determined that, unlike in the virus-infected host where MOTRC1 pathway is diminished, Slc7a5 deficiency leads to decreased AhR signaling and FasL expression in tumor-infiltrating T cells. Accordingly, FasL blockade increased lung metastases in breast tumor-bearing mice and increased tumor growth in melanoma tumor-bearing mice, indicating that Slc7a5 regulates the tryptophan-AhR metabolic pathway to regulate FasL expression in T cells to control tumor-infiltrating CTL effector function. Analysis of scRNA-seq dataset of human breast cancer patients revealed that FasL expression in T cells is correlated with SLC7A5 expression and patient response to immune checkpoint inhibitor immunotherapy. Furthermore, FasL is positively correlated with patient survival length in pooled datasets of 33 human cancers, and in human patients with breast cancer and melanoma in particular. Our findings determine that Slc7a5 controls tryptophan uptake in tumor-infiltrating CTLs to regulate the tryptophan-AhR metabolic pathway to regulate FasL expression to control CTL anti-tumor immune response.
2025-05-17 | GSE267838 | GEO
Project description:Long-term survival of cardiac transplant recipients remains a significant hurdle largely due to cardiac allograft vasculopathy (CAV) as an expression of chronic rejection (CR). Currently, coronary angiography and intravascular ultrasound, invasive and expensive modalities, are considered the standard for diagnosis of CAV. In the current study, we combined assessment of blood mRNA and proteins to identify potential biomarkers for diagnosis of CAV. Whole blood Affymetrix microarrays and plasma iTRAQ-MALDI-TOF/TOF proteomic analyses were carried out on 25 cardiac transplant patient samples. CAV diagnosis was made based on blinded quantitative analysis of angiograms, intravascular ultrasound images and clinical chart review. The genomics and proteomics data were assessed by moderated t-tests and discriminant analysis. Two panels of 10 differentially expressed genes (FDR<5%), and 10 proteins with differential relative levels (p-values<0.025) between CAV and non-CAV samples were independently identified. Classification of new test samples revealed that the 10 genes together can discriminate between CAV and non-CAV samples with 83% sensitivity and specificity. Classification of the same samples using the 10 PGC’s dropped the sensitivity to 67%. A combinatorial panel derived from the genomic and proteomic panels provided improvement in performance, at 100% sensitivity and 83% specificity. Leave-one-out cross validation showed similar results. Genomic, proteomic and combinatorial blood-based biomarkers are promising as potential minimally-invasive, sensitive and specific modalities for the diagnosis of CAV. Classifier panels generated from current work are being evaluated in a prospective, multi-site observational trial.
2020-09-01 | GSE18656 | GEO
Project description:Cardiac allograft vasculopathy (CAV) is the leading cause of mortality in heart transplant recipients. Despite the prevalence of CAV, there are no targeted therapeutic options to prevent or reverse disease progression, and patients ultimately require retransplant. CAV is characterized by progressive neointimal hyperplasia in donor heart coronary arteries, leading to luminal obliteration and ultimately allograft failure or sudden cardiac death. Although immune and stromal cell interactions are believed to play a key role in CAV pathogenesis, the specific cellular players and molecular signals driving disease remain undefined. In this study, we leverage single-cell RNA sequencing and spatial transcriptomics of human coronary arteries to transcriptionally characterize CAV and define the neointimal microenvironment. We compare arteries with CAV to atherosclerotic coronary artery disease and non-disease controls to identify a unique CAV transcriptional signature. Integration of single-cell RNA sequencing and spatial transcriptomic datasets revealed that modulated vascular smooth muscle cells and macrophage subsets dominate the CAV neointima and suggest that these cells interact to propagate type 1 interferon (IFN)-mediated inflammation. In a mouse CAV model, we demonstrate that interferon blockade with Ruxolitinib significantly reduced the incidence of CAV and prolonged allograft survival. Collectively, this study offers a novel and detailed characterization of the unique cellular and transcriptional landscape of CAV and identify a candidate pathway that may underly CAV pathogenesis, which could serve as a new therapeutic target for this devastating disease.
2026-03-06 | GSE316390 | GEO