Expression profile of shMCT-1 in 4T1 metastatic murine triple-negative breast cancer (TNBC) cell lines in response to anti-IL6R immunotherapy
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ABSTRACT:
PROVIDER: PRJNA995548 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25309815_1.fastq.gz | Fastqsanger.gz | |||
| SRR25309815_2.fastq.gz | Fastqsanger.gz | |||
| SRR25309816_1.fastq.gz | Fastqsanger.gz | |||
| SRR25309816_2.fastq.gz | Fastqsanger.gz | |||
| SRR25309817_1.fastq.gz | Fastqsanger.gz |
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Project description:Malignant T-cell amplified sequence (MCT-1 or MCTS1) is an oncoprotein that regulates translation re-initiation, ribosomal recycling, and tumorigenicity. Given that MCT-1 amplifies interleukin-6 (IL-6) trans-signaling by elevating interaction between interleukin-6 receptor (IL-6R) and glycoprotein 130 (gp130), we aimed to dissect whether targeting IL-6R alters transcriptional profile of TNBC cells with different MCT-1 background. Through RNA-seq, we have characterized that anti-IL6R immunotherapy suppressed genes involved in cell proliferation and metastatic cascades but enriched genes associated in cell adhesion in 4T1 murine TNBC cells with shMCT-1.
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Project description:Immunotherapy is a breakthrough in the treatment of triple-negative breast cancer (TNBC), whereas is effective in a portion of patients. Our clinical studies found that lipid homeostasis imbalance and dendritic cells (DCs) dysfunction contributed to the immunosuppressive microenvironment in the lymph nodes (LNs) of TNBC patients following immunotherapy, which greatly affected the immunotherapeutic efficacy. Building on this, we introduce a chimeric exosomes-derived immunomodulator, EMV@SS-Toy, involving a polysulfide bond-bridged mesoporous silica nanoparticles (SS-MSN) as a reactive oxygen species (ROS) scavenger and responsive carrier nucleus, loading with the (IRE1α-XBP1) inhibitor toyocamycin (Toy) and coating with chimeric exosomes comprising DCs-derived exosomes and Salmonella outer membrane vesicles. This multifaceted immunomodulator can significantly enhance LNs’ homing via homologous targeting and chemokine-guided navigation, enabling a pathological ROS-responsive drug release, dual-stress pathway regulation, thereby restoring and DCs’ function and LNs’ immune microenvironment. As expected, the immunomodulator markedly boosted the responsiveness of TNBC to immunotherapy, exerting potent inhibition on both the primary tumor and metastases and establishing long-term immune surveillance. Our study provides potent directions for translational immunotherapy through optimizing the LNs’ microenvironment in TNBC.
2024-10-01 | GSE270025 | GEO
Project description:Tumor-associated macrophages (TAMs) are closely related to poor prognosis in triple-negative breast cancer (TNBC). Thus, gaining insight into how TAMs support cancer progression could contribute to effective therapies. We utilized the 4T1 murine TNBC cell line and murine bone marrow-derived macrophages to assess TAMs mediated pro-proliferative effects in vivo and in vitro. Further, Transcriptional analysis was performed to identify pathways activated in TAMs stimulated 4T1 cells. To simulate tumor microenvironment, M2 macrophages and 4T1 cells were plated into upper and lower chambers of Transwell co-culture systems respectively. we performed RNA-sequencing analysis of 4T1 cells incubated with vehicle control or M2 macrophages.
2019-07-25 | GSE134787 | GEO
Project description:Expression profile of shMCT-1 in 4T1 metastatic murine triple-negative breast cancer (TNBC) cell lines
| PRJNA852594 | ENA
Project description:MCT-1 (malignant T cell amplified sequence) is an oncoprotein encoded by Mcts1 gene that regulates translation re-initiation, ribosomal recycling, and tumorigenicity. We have characterized the metastasis cascade, immune evasion,and inflammatory responses which are suppressed by silencing of MCT-1 (shMCT-1) through transcriptional profiling of the 4T1 metastatic TNBC cell line. shMCT-1-altered gene lists are related to the IFNα-response, IFNγ-response, IL-6/JAK/STAT pathway, inflammatory response. shMCT-1 also suppresses expression of upstream regulators of PD-L1 and epidermal growth factor receptor (EGFR) ligands as compared to scramble cells.
2022-06-25 | GSE206910 | GEO
Project description:Recent meta-analyses suggest triple-negative breast cancer (TNBC) is a heterogenous disease. In this study we sought to define these TNBC subtypes and identify subtype-specific markers and targets. We identified and confirmed four distinct, stable TNBC subtypes: (1) Luminal-AR (LAR); 2) Mesenchymal (MES); 3) Basal-Like Immune-Suppressed (BLIS), and 4) Basal-Like Immune-Activated (BLIA). RNA profiling analysis was conducted on 198 TNBC tumors (ER-negativity defined as Allred Scale value â¤2) with >50% cellularity (discovery set: n=84; validation set: n=114)
2015-12-18 | E-GEOD-76124 | biostudies-arrayexpress
Project description:Novel therapies targeting cancer stem cells (CSCs), which play critical roles in chemo- and radio-resistance, metastasis, and possibly resistance against cancer immunotherapy including granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced tumor cell vaccines, may provide beneficial clinical outcomes. Here, we used syngeneic immunocompetent mice that allowed precise evaluation of the immunogenicity of the side population (SP) isolated from 4T1 murine breast carcinoma (4T1-SP) cells as putative CSCs. 4T1-SP cells showed various stem cell properties including high capacities for colony formation and tumorigenicity as well as high expression of phosphorylated signal transducer and activator of transcription-3 and vascular endothelial growth factor that are inductive of immune tolerance. Despite these progressive malignant characteristics of 4T1-SP cells, subcutaneous injection of non-transmissible Sendai virus-mediated GM-CSF gene-transduced 4T1-SP (4T1-SP/GM) cells remarkably impaired their tumorigenicity compared with that of the controls. This impairment of tumorigenicity was partially dependent on CD8+ T cells in concert with CD4+ T cells and natural killer cells. Notably, therapeutic vaccinations using irradiated 4T1-SP/GM cells markedly suppressed tumor development of subcutaneously transplanted 4T1-SP cells compared with that of the controls including irradiated 4T1-non-SP/GM cells. Tumor suppression was accompanied by robust accumulation of mature dendritic cells at vaccination sites and systemic Th1-based cellular immunity. Moreover, vaccinations comprising primary 4T1-SP cells isolated from transplanted 4T1-SP tumors elicited antitumor effects. cDNA microarray analysis showed that 4T1-SP cells predominantly expressed genes of cancer-related antigens including cancer/testis antigens. Collectively, we demonstrate that SP cell-based vaccinations induce effective antitumor immunity that may improve the efficacy of SP cell-based immunotherapy. Gene expression profiles were compared between sorted 4T1-SP and 4T1-NSP cells.
2014-04-01 | E-GEOD-53444 | biostudies-arrayexpress
Project description:Purpose: Compare the tumor outgrowth and immunology of an immunocompetent 4T1- and Py230-based intraductal model for triple-negative breast cancer (TNBC). Methods: BALB/c-derived 4T1 and C57BL/6-derived Py230 mammary tumor cells were side-by-side intraductally inoculated in lactating and syngeneic mice, 4T1 and Py230 primary tumors were subsequently resected at 1, 3 and 6 weeks (w) post-inoculation (p.i.), and RNA was isolated from the 4T1 and Py230 primary tumors using in house developed protocols. Results: The differentially expressed genes in the 4T1 versus Py230 primary tumor datasets at the 3 different time points were categorized into 28 hallmark gene sets using GSEA. Nine hallmarks could be related to tumor immunology and collectively showed a decreased difference in expression over time, although every immunology-related gene set remained most expressed in 4T1 primary tumors across all time points. Seven hallmarks could be related to cellular mitosis and tumor progression and were significantly upregulated at 1 w p.i. in 4T1 primary tumors, whereas at 3 w p.i. they became significantly upregulated in Py230 primary tumors, indicative for enhanced Py230 tumor proliferation. The hallmark epithelial-mesenchymal transition was significantly upregulated at 3 w p.i. in 4T1 compared to Py230 primary tumors, indicative for metastatic progression. Gene sets involved in adipose/stromal processes within the mammary gland were downregulated or weakly expressed at 1 w p.i., but became upregulated at 3 w p.i. in 4T1 compared to Py230 primary tumors, indicating that at the time 4T1 tumor cells were less proliferative compared to Py230 tumor cells, the surrounding stroma and fat tissue were more active in the 4T1- compared to the Py230-based intraductal model. The hallmark androgen response also showed a significantly upregulated expression in Py230 tumors at 3 and 6 w p.i., indicating that androgen signaling is important in invasive Py230 tumors. Conclusion: Our findings highlight an innovative 4T1- and Py230-based intraductal mouse model for TNBC with a different tumor outgrowth and associated tumor microenvironment. These differential models may broadly represent the clinically observed TNBC diversity and together provide a powerful tool to evaluate therapeutics.
2019-11-20 | GSE140192 | GEO
Project description:We identified the SOX4 transcription factor and integrin alpha V encoded by the ITGAV gene as important resistance mechanisms to T cell-mediated cytotoxicity of TNBC cells. Here, we performed RNA seq. analysis of SOX4 and ITGAV deficient (CRISPR knockout) BT549 human and 4T1 murine TNBC cells as compared to control edited counterparts. Additionally, we performed SOX4 specific ChIP-seq studies in BT549 human TNBC cells. The objective of the study was to identify the molecular regulators and signaling pathways that mediate resistance to T cell mediated immunity. GSEA analysis of RNA-seq data showed that the 'interferon response' represented one of the top pathways for genes upregulated in SOX4 or ITGAV edited compared to control TNBC cells. In contrast, gene sets associated with TGF beta and TNF alpha/NF kappa b were negatively enriched in both Sox4 and Itgav edited TNBC cells. Further analysis of RNA-seq data showed that SOX4 or ITGAV edited TNBC cells contained higher mRNA levels of many interferon-stimulated genes (ISGs), including genes associated with important innate immune pathways such as RIG-I/MDA-5, cGAS - STING and the AIM2 inflammasome
2021-01-01 | GSE144013 | GEO
Project description:Immune therapy has emerged as the new frontier of cancer treatment. Therapeutic radiation is a known inducer of an immune response that can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2), which is highly expressed in triple negative breast tumors. A clinical cohort of triple negative breast cancer (TNBC) tumors revealed that elevated COX2 tumor expression predicted poor radiation therapeutic efficacy. Using the aggressive murine 4T1 TNBC model, we show that treatment with ionizing radiation and adjuvant NSAID (indomethacin) therapy to inhibit COX2 provides a powerful combination to reduce both primary tumor growth and lung metastasis through immune modulation. Using whole tumor RNAseq and multiplex fluorescence imaging, this study reveals spatial immunological changes in the treated primary tumor. Indomethacin alone increased the infiltration of lymphoid populations into the primary tumor. Importantly, the combined treatment improved lymphoid infiltration into the tumor epithelium, augmented cGAS/STING1 and type I IFN gene expression and altered key immune checkpoints including PD1, IDO, and CTLA4. Markedly increased B cell and T cell populations with increased CD8+ T cell activation and reduced T cell exhaustion were observed. Thus, adjuvant NSAID treatment combined with radiation therapy shifts “immune desert phenotypes” toward anti-tumor immune mediators favoring M1/Th1 signatures in the immunologically challenging 4T1 tumor model. Importantly, radiation/indomethacin combination improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared to mice treated with single agent radiation. These results show that clinically available NSAID’s augment radiation therapeutic efficacy through improved antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs
2024-05-28 | GSE264712 | GEO