MLK4 regulates macrophage-induced gene expression changes associated with extracellular matrix remodeling, cell adhesion, and invasion
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE304746 | GEO | 2025/09/03
REPOSITORIES: GEO
Similar Datasets
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:Glucocorticoids (GCs) are known for their anti-inflammatory potential, which includes macrophage polarization into an anti-inflammatory and tissue remodeling state. GCs are routinely co-administered to cancer patients to alleviate the side effects of chemotherapy. However, it is not well known if GCs can modulate tumor-associated macrophages (TAMs) to promote tumor progression. Here, we show that dexamethasone (DEX) induces dose-dependent differentiation of THP-1 monocyte-derived anti-tumorigenic (M1) macrophages into pro-tumorigenic (M2-like) macrophages, even in the presence of M1 cues, and that DEX can repolarize fully differentiated M1 macrophages into an M2-like state. These macrophages have a cytokine profile similar to the pro-tumorigenic (M2) macrophages and can stimulate the proliferation and invasion of triple-negative breast cancer (TNBC) cells in vitro. DEX treatment of an orthotopic mouse model of TNBC attenuated paclitaxel-mediated tumor growth inhibition, increased M2-like TAMs in primary tumors, and enhanced lung metastasis. Transcriptomic analysis of DEX-treated M1 macrophages revealed not only transcriptomic overlap to M2 macrophages, but to human breast cancer TAM transcriptomic data and further to a specific TAM signature associated with aggressive estrogen receptor-negative breast cancer. Our study illustrates a remarkable macrophage repolarization plasticity upon DEX exposure and warrants care in prescribing high doses of GCs to breast cancer patients, especially to those considered for chemotherapy.
2025-03-05 | GSE290519 | GEO
Project description:Macrophages have been implicated in breast cancer progression and metastasis, but relatively little is known about the genes and pathways that are involved. Using a conditional allele of Ets2 in the mouse, we have identified Ets2 as a critical gene in tumor associated macrophages (TAMs) that specifically promotes mammary tumor metastasis. Loss of Ets2 in TAMs decreased the frequency and size of lung metastases without impacting primary tumor burden. Expression profiling of isolated tumor macrophages established that Ets2 deficiency resulted in the de-repression of a defined set of anti-angiogenic genes. Activation of this transcriptional program correlated with decreased angiogenesis in metastatic tumors and decreased metastatic growth. Comparison of this Ets2-specific TAM expression profile with human breast cancer profiles revealed a macrophage gene expression signature that could predict overall survival of estrogen receptor negative patients. In summary, we have identified a critical factor, Ets2, in TAMs that represses a transcriptional program to promote the growth of mammary tumor metastases in the lung. Breast TAMs were isolated from early-stage PyMT-induced mammary tumors expressing Ets2 and also from the tumors with Ets2-deficient TAMs. Since macrophages have also been implicated in normal mammary gland remodeling, normal remeodeling macrophages were also purified from females expressing Ets2 and the ones where Ets2 is deleted in the macrophages. One RNA sample was extracted from each genetic group for gene-expression profiling.
2010-01-05 | E-GEOD-12863 | biostudies-arrayexpress
Project description:Metastasis remains the leading cause of cancer-related mortality, driven by complex interactions within the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play a pivotal role in metastatic progression, yet molecular diversity and upstream regulators remain poorly defined. Glycoprotein nonmetastatic melanoma protein B (GPNMB), overexpressed in subsets of tumors including triple-negative breast cancer (TNBC), is implicated in epithelial-mesenchymal transition (EMT) and cancer stemness. Recent single-cell RNA-seq studies have identified GPNMB as a marker of immunosuppressive TAMs associated with poor prognosis, but its mechanistic role in TAM polarization in TNBC has remained unclear. Co-culturing monocytic cells with three-dimensional sphere-forming TNBC cells induces their conversion into GPNMB⁺Siglec-9⁺ tumor-associated macrophages (TAMs). Tumor-derived GPNMB promotes monocyte-to-TAM polarization by inducing secondary GPNMB expression in monocytes, establishing a feed-forward amplification loop. Knockdown of GPNMB in TNBC cells significantly inhibits multiple immunosuppressive TAM subtypes, including Siglec-9⁺ TAM and EMT-associated TAM populations, as inferred from scRNA-seq and validated in patient tumors using bulk RNA-seq deconvolution. Distinct sialylation patterns were identified: tumor-derived GPNMB exhibited α2,3-sialylation, whereas macrophage-derived GPNMB exhibited α2,6-sialylation, enabling differential Siglec-9 recognition. Elevated GPNMB and Siglec-9 expression correlated with poor prognosis in TNBC patient cohorts. Importantly, dual inhibition of Siglec-E (murine Siglec-9 ortholog) and PD-1 suppressed IL-6-dependent EMT, reduced tumor stemness, and significantly limited lung metastasis in vivo. The GPNMB–Siglec-9 axis thus represents a critical glyco-immunological checkpoint driving TAM-mediated metastasis, providing a promising therapeutic target in TNBC.
2025-08-15 | GSE271964 | GEO
Project description:Metastasis remains the leading cause of cancer-related mortality, driven by complex interactions within the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play a pivotal role in metastatic progression, yet molecular diversity and upstream regulators remain poorly defined. Glycoprotein nonmetastatic melanoma protein B (GPNMB), overexpressed in subsets of tumors including triple-negative breast cancer (TNBC), is implicated in epithelial-mesenchymal transition (EMT) and cancer stemness. Recent single-cell RNA-seq studies have identified GPNMB as a marker of immunosuppressive TAMs associated with poor prognosis, but its mechanistic role in TAM polarization in TNBC has remained unclear. Co-culturing monocytic cells with three-dimensional sphere-forming TNBC cells induces their conversion into GPNMB⁺Siglec-9⁺ tumor-associated macrophages (TAMs). Tumor-derived GPNMB promotes monocyte-to-TAM polarization by inducing secondary GPNMB expression in monocytes, establishing a feed-forward amplification loop. Knockdown of GPNMB in TNBC cells significantly inhibits multiple immunosuppressive TAM subtypes, including Siglec-9⁺ TAM and EMT-associated TAM populations, as inferred from scRNA-seq and validated in patient tumors using bulk RNA-seq deconvolution. Distinct sialylation patterns were identified: tumor-derived GPNMB exhibited α2,3-sialylation, whereas macrophage-derived GPNMB exhibited α2,6-sialylation, enabling differential Siglec-9 recognition. Elevated GPNMB and Siglec-9 expression correlated with poor prognosis in TNBC patient cohorts. Importantly, dual inhibition of Siglec-E (murine Siglec-9 ortholog) and PD-1 suppressed IL-6-dependent EMT, reduced tumor stemness, and significantly limited lung metastasis in vivo. The GPNMB–Siglec-9 axis thus represents a critical glyco-immunological checkpoint driving TAM-mediated metastasis, providing a promising therapeutic target in TNBC.
2025-08-15 | GSE270890 | GEO
Project description:Efforts to improve the clinical outcome of highly aggressive triplenegative breast cancer (TNBC) have been hindered by the lack of effective targeted therapies. Hence, it is important to identify the specific gene targets/pathways driving the invasive phenotype to develop more effective therapeutics. Here we show that UBASH3B (ubiquitin associated and SH3 domain containing B), a protein tyrosine phosphatase, is overexpressed in TNBC, where it supports malignant growth, invasion and metastasis in large through modulating EGFR. We also show that UBASH3B is a functional target of anti-invasive miR-200a that is downregulated in TNBC. Importantly, the oncogenic potential of UBASH3B is dependent on its tyrosine phosphatase activity, which targets CBL ubiquitin ligase for dephosphorylation and inactivation, leading to EGFR upregulation. Thus, UBASH3B may function as a crucial node in bridging multiple invasion-promoting pathways, thus providing a potential new therapeutic target for TNBC. Breast cancer tissues and breast cancer cell lines
2013-06-01 | E-GEOD-36693 | biostudies-arrayexpress
Project description:Clinical and experimental evidence indicates that tumor-associated macrophages (TAMs) promote malignant progression. In breast cancer, TAMs enhance tumor angiogenesis, tumor cell invasion, matrix remodeling, and immune suppression against the tumor. In this study, we examined late-stage mammary tumors from a transgenic mouse model of breast cancer. We used flow cytometry under conditions that minimized gene expression changes to isolate a rigorously defined TAM population previously shown to be associated with invasive carcinoma cells. The gene expression signature of this population was compared with a similar population derived from spleens of non-tumor-bearing mice using high-density oligonucleotide arrays. Using stringent selection criteria, transcript abundance of 460 genes was shown to be differentially regulated between the two populations. Bioinformatic analyses of known functions of these genes indicated that formerly ascribed TAM functions, including suppression of immune activation and matrix remodeling, as well as multiple mediators of tumor angiogenesis, were elevated in TAMs. Further bioinformatic analyses confirmed that a pure and valid TAM gene expression signature in mouse tumors could be used to assess expression of TAMs in human breast cancer. The data derived from these more physiologically relevant autochthonous tumors compared with previous studies in tumor xenografts suggest tactics by which TAMs may regulate tumor angiogenesis and thus provide a basis for exploring other transcriptional mediators of TAM trophic functions within the tumor microenvironment. Tumor-associated macrophages from late-stage mouse mammary tumors compared to splenic macrophages from non-tumor-bearing littermate controls. 4 biological replicates of each population were compared via gene expression arrays.
2010-06-21 | E-GEOD-18404 | biostudies-arrayexpress
Project description:Tumor associated macrophages (TAMs), which differentiate from circulating monocytes, are pervasive across human cancers and comprise heterogeneous populations. The contribution of tumor-derived signals to TAM heterogeneity is not well understood. In particular, tumors release both soluble factors and extracellular vesicles (EVs), whose respective impact on TAM precursors may be different. Here, we show that triple negative breast cancer cells (TNBC) release EVs and soluble molecules promoting monocyte differentiation towards distinct macrophage fates.
2022-03-16 | GSE173771 | GEO
Project description:Triple negative breast cancer (TNBC) poorly responds to immune checkpoint blockade (ICB) therapy. Dormant tumor cells are recognized as immunotherapy-resistant reservoirs, potential leading to tumor relapse, highlighting the importance to elucidate the mechanisms underlying immunotherapy resistance. Herein, we demonstrated that dormant tumor cells were resistant to ICB therapy and occupied an immunosuppressive niche with enhanced tumor-associated macrophages (TAMs) and decreased CD8+T cells infiltration in mouse TNBC allografts via a label-retention system. CEBPB was highly expressed in dormant tumor cells and maintained tumor dormancy by transcriptionally activating cell cycle negative regulators like CCNG2 and p27.
2025-02-21 | GSE290039 | GEO
Project description:Triple negative breast cancer (TNBC) poorly responds to immune checkpoint blockade (ICB) therapy. Dormant tumor cells are recognized as immunotherapy-resistant reservoirs, potential leading to tumor relapse, highlighting the importance to elucidate the mechanisms underlying immunotherapy resistance. Herein, we demonstrated that dormant tumor cells were resistant to ICB therapy and occupied an immunosuppressive niche with enhanced tumor-associated macrophages (TAMs) and decreased CD8+T cells infiltration in mouse TNBC allografts via a label-retention system. CEBPB was highly expressed in dormant tumor cells and maintained tumor dormancy by transcriptionally activating cell cycle negative regulators like CCNG2 and p27.
2025-02-21 | GSE290038 | GEO