Prune-1 drives polarization of tumor-associated macrophages (TAMs) within the lung metastatic niche in triple-negative breast cancer.
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ABSTRACT:
SUBMITTER: Ferrucci V
PROVIDER: S-EPMC7779777 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeTo investigate the mechanism underlying the modulation of M1 macrophage polarization by exosomes released from hyperthermia-treated triple-negative breast cancer (TNBC) cells.Materials and methodsIn this study, the effects of hyperthermia on TNBC cells were examined using cell counting kit-8, apoptosis, and cell cycle assays. Transmission electron microscopy was used to identify the structure of exosomes, while bicinchoninic acid and nanoparticle tracking analysis were used to detect particle size and amounts of exosomes released after hyperthermia. The polarization of macrophages incubated with exosomes derived by hyperthermia-pretreated TNBC cells were assessed by RT-qPCR and flow cytometry analysis. Next, RNA sequencing was performed to determine the targeting molecules changed in hyperthermia-treated TNBC cells in vitro. Finally, the mechanism underlying the modulation of macrophage polarization by exosomes derived from hyperthermia-treated TNBC cells was examined by using RT-qPCR, immunofluorescence and flow cytometry analysis.ResultsHyperthermia markedly reduced cell viability in TNBC cells and promoted the secretion of TNBC cell-derived exosomes. The hub genes of hyperthermia-treated TNBC cells were significantly correlated with macrophage infiltration. Additionally, hyperthermia-treated TNBC cell-derived exosomes promoted M1 macrophage polarization. Furthermore, the expression levels of heat shock proteins, including HSPA1A, HSPA1B, HSPA6, and HSPB8, were significantly upregulated upon hyperthermia treatment, with HSPB8 exhibiting the highest upregulation. Moreover, hyperthermia can induce M1 macrophage polarization by promoting exosome-mediated HSPB8 transfer.ConclusionThis study demonstrated a novel mechanism that hyperthermia can induce M1 polarization of macrophages via exosome-mediated HSPB8 transfer. These results will help with future development of an optimized hyperthermia treatment regime for clinical application, especially for combination treatment with immunotherapy.
| S-EPMC10219922 | biostudies-literature
Project description:Here, we evaluated the effect of Pleiotrophin (PTN) depletion on tumor microenvironment. For this, we utilized a mouse monoclonal antibody against PTN, 3B10. We tested its therapeutic efficacy in 2 mouse breast cancer models, 4T1 (orthotopic, 4th mammary fat pad) and MMTV-PyMT (genetic model). Tumors from control IgG(C44) treated and 3B10 treated mice were sent for RNA sequencing to evaluate transcriptional changes. Additionally, PTN was knocked down in E0771 and E0771-LG syngeneic breast cancer lines. To evaluate transcriptional changes due to PTN depletion, shCtrl and PTN KD cells from E0771 and E0771-LG were evaluated by RNA sequencing. Overall, our results from these 4 sets of experiments show that depletion or blocking PTN results in inflammation related transcript changes suggesting function of PTN in immune regulation.
2023-02-16 | GSE200431 | GEO
Project description:Epithelial-Mesenchymal plasticity plays a fundamental role both in embryogenesis and in tumor cell dissemination during tumor progression. The receptor for advanced glycation end products (RAGE) is a driver of cell plasticity in fibrotic diseases; however, its role and molecular mechanism in triple-negative breast cancer (TNBC) remains unclear. Here, we demonstrate that RAGE signaling maintains the mesenchymal phenotype of aggressive TNBC cells by enforcing the expression of SNAIL. We uncover a crosstalk mechanism between the TGF-β and RAGE pathways that is required for the acquisition of mesenchymal traits in TNBC cells. Consistently, RAGE inhibition elicits epithelial features that block migration and invasion capacities. Since RAGE is a sensor of the tumor microenvironment (TME) and the highly glycolytic rate of tumors induces an acidic TME, we modeled acute acidosis in TNBC cells and showed it promotes enhanced production of RAGE ligands and the activation of RAGE-dependent invasive properties. Furthermore, acute acidosis increases SNAIL levels and tumor cell invasion in a RAGE-dependent manner. Finally, we demonstrate that in vivo inhibition of RAGE reduces metastasis incidence and expands survival, consistent with molecular effects that support the relevance of RAGE signaling in EMT plasticity. These results uncover new molecular insights on the regulation of EMT phenotypes in cancer metastasis and provide rationale for pharmacological intervention of this signaling axis.
2023-12-28 | GSE223229 | GEO
Project description:Production of metastasis capable precursors begins within the primary tumor. Here, we define the bidirectional interactions with stromal cells involved in promoting these precursors within BRCA1-IRIS (hereafter IRIS) overexpressing (IRISOE) TNBC tumors. We define an aggressiveness niche, functionally defined as the necrotic/hypoxic core of the tumor, in which metabolically stressed, hypoxic, and inflamed IRISOE TNBC cells secrete higher levels of cytokines, chemokines and growth factors. One cytokine; IL-1? attracts mesenchymal stem cells (MSCs) to the niche and activates them to secrete CXCL1 that entrains IRISOE cells to secrete higher levels of CCL2 and VEGF. CCL2 attracts macrophages (TAMs) to the niche and activates them to secrete S100A8, and VEGF attracts endothelial cells (ECs) and activates them to secrete IL-8. In concert, CXCL1, S100A8 and IL-8 entrain aggressiveness in IRISOE TNBC cells within the niche. Indeed, compared to IRISOE cells alone, tumors developed by co-injecting IRISOE cells admixed with MSCs (10:1) in athymic mice were bigger and more aggressive. They contained more TAMs and ECs, expressed higher-levels of basal, epithelial to mesenchymal transition, and stemness biomarkers, quickly progressed to lymph-node or visceral metastases, and were highly sensitive to the IL-1? inhibitor "Anakinra". Our findings supported by human data show that breast cancer patients with high-levels of IL-1?, CXCL1, CCL2, S100A8, VEGF, and IL-8 would show worse clinical outcomes. Our findings argue that this cytokine set is a diagnostic biomarker for patients who may benefit from an IRIS inhibitor-based therapy, and is a blue print for translation of approaches to combining that therapy with inhibitors of these bidirectional interactions to overcome TNBC metastasis.
| S-EPMC5732721 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) has been subdivided into six distinct subgroups: basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M), mesenchymal stem-like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR). We recently identified a subgroup of TNBC with loss of the tumor suppressor PTEN and five specific microRNAs that exhibits exceedingly poor clinical outcome and contains TP53 mutation, RB1 loss and high MYC and WNT signalling. Here, show that these PTEN-low/miRNA-low lesions cluster with BL1 TNBC. These tumors exhibited high RhoA signalling and were significantly stratified on the basis of PTEN-low/RhoA-signalling-high with hazard ratios (HRs) of 8.2 (P?=?0.0009) and 4.87 (P?=?0.033) in training and test cohorts, respectively. For BL2 TNBC, we identified AKT1 copy gain/high mRNA expression as surrogate for poor prognosis (HR?=?3.9; P?=?0.02 and HR?=?6.1; P?=?0.0032). In IM, programmed cell death 1 (PD1) was elevated and predictive of poor prognosis (HR?=?5.3; P?=?0.01 and HR?=?3.5; P?<?0.004). Additional alterations, albeit without prognostic power, characterized each subtype including high E2F2 and TGF? signalling and CXCL8 expression in BL2, high IFN? and IFN? signalling and CTLA4 expression in IM, and high EGFR signalling in MSL, and may be targeted for therapy. This study identified PTEN-low/RhoA-signalling-high, and high AKT1 and PD1 expression as potent prognostications for BL1, BL2 and IM subtypes with survival differences of over 14, 2.75 and 10.5 years, respectively. This intrinsic heterogeneity could be exploited to prioritize patients for precision medicine.
| S-EPMC6911070 | biostudies-literature
Project description:BackgroundTumor-associated macrophages (TAM) are immunosuppressive cells that contribute to impaired anti-cancer immunity. Iron plays a critical role in regulating macrophage function. However, it is still elusive whether it can drive the functional polarization of macrophages in the context of cancer and how tumor cells affect the iron-handing properties of TAM. In this study, using hepatocellular carcinoma (HCC) as a study model, we aimed to explore the effect and mechanism of reduced ferrous iron in TAM.MethodsTAM from HCC patients and mouse HCC tissues were collected to analyze the level of ferrous iron. Quantitative real-time PCR was used to assess M1 or M2 signature genes of macrophages treated with iron chelators. A co-culture system was established to explore the iron competition between macrophages and HCC cells. Flow cytometry analysis was performed to determine the holo-transferrin uptake of macrophages. HCC samples from The Cancer Genome Atlas (TCGA) were enrolled to evaluate the prognostic value of transferrin receptor (TFRC) and its relevance to tumor-infiltrating M2 macrophages.ResultsWe revealed that ferrous iron in M2-like TAM is lower than that in M1-like TAM. In vitro analysis showed that loss of iron-induced immunosuppressive M2 polarization of mouse macrophages. Further experiments showed that TFRC, the primary receptor for transferrin-mediated iron uptake, was overexpressed on HCC cells but not TAM. Mechanistically, HCC cells competed with macrophages for iron to upregulate the expression of M2-related genes via induction of HIF-1α, thus contributing to M2-like TAM polarization. We further clarified the oncogenic role of TFRC in HCC patients by TCGA. TFRC is significantly increased in varieties of malignancies, including HCC, and HCC patients with high TFRC levels have considerably shortened overall survival. Also, TFRC is shown to be positively related to tumor-infiltrating M2 macrophages.ConclusionsCollectively, we identified iron starvation through TFRC-mediated iron competition drives functional immunosuppressive polarization of TAM, providing new insight into the interconnection between iron metabolism and tumor immunity.
| S-EPMC8361643 | biostudies-literature
Project description:Aim: The aim of our study was to explore the pathophysiologic role of oxidation of hemoglobin (Hb) to ferrylHb in human atherosclerosis. Results: We observed a severe oxidation of Hb to ferrylHb in complicated atherosclerotic lesions of carotid arteries with oxidative changes of the globin moieties, detected previously described oxidation hotspots in Hb (β1Cys93; β1Cys112; β2Cys112) and identified a novel oxidation hotspot (α1Cys104). After producing a monoclonal anti-ferrylHb antibody, ferrylHb was revealed to be localized extracellularly and also internalized by macrophages in the human hemorrhagic complicated lesions. We demonstrated that ferrylHb is taken up via phagocytosis as well as CD163 receptor-mediated endocytosis and then transported to lysosomes involving actin polymerization. Internalization of ferrylHb was accompanied by upregulation of heme oxygenase-1 and H-ferritin and accumulation of iron within lysosomes as a result of heme/iron uptake. Importantly, macrophages exposed to ferrylHb in atherosclerotic plaques exhibited a proinflammatory phenotype, as reflected by elevated levels of IL-1β and TNF-α. To find further signatures of ferrylHb in complicated lesions, we performed RNA-seq analysis on biopsies from patients who underwent endarterectomies. RNA-seq analysis demonstrated that human complicated lesions had a unique transcriptomic profile different from arteries and atheromatous plaques. Pathways affected in complicated lesions included gene changes associated with phosphoinositide 3-kinase (PI3K) signaling, lipid transport, tissue remodeling, and vascularization. Targeted analysis of gene expression associated with calcification, apoptosis, and hemolytic-specific clusters indicated an increase in the severity of complicated lesions compared with atheroma. A 39% overlap in the differential gene expression profiles of human macrophages exposed to ferrylHb and the complicated lesion profiles was uncovered. Among these 547 genes, we found inflammatory, angiogenesis, and iron metabolism gene clusters regulated in macrophages. Innovation and Conclusion: We conclude that oxidation of Hb to ferrylHb contributes to the progression of atherosclerosis via polarizing macrophages into a proatherogenic phenotype. Antioxid. Redox Signal. 35, 917-950.
| S-EPMC8905252 | biostudies-literature
Project description:Metastatic triple-negative breast cancer (TNBC) is a distinct and immensely complex form of breast cancer. Among all subtypes of breast cancers, TNBC has a comparatively high rate of relapse, a high rate of distant metastasis, and poor overall survival after standard chemotherapy. Chemotherapy regimens are an essential component of the management of this estrogen receptor-negative, progesterone receptor-negative, and epidermal growth factor receptor2 negative subtype of breast cancers. Chemotherapy is critical for preventing the recurrence of the disease and for achieving long-term survival. Currently, a couple of agents are approved for the management of this disease, including chemotherapy like eribulin, targeted therapy like PARP inhibitor, as well as an antibody-drug conjugate (ADC) to target TROP2. Like many other metastatic cancers, immune checkpoint inhibitors (ICIs) have also been approved for TNBC patients with PD-L1 positive tumors and high tumor mutational burden. In this review article, we discuss these newly approved and promising novel agents that may change the therapeutic landscape for advanced/metastatic TNBC patients.
| S-EPMC8150754 | biostudies-literature
Project description:In contrast to primary tumors, the understanding of macrophages within metastases is very limited. In order to compare macrophage phenotypes between different metastatic sites, we established a pre-clinical mouse model of intracranial breast cancer metastasis in which cancer lesions develop simultaneously within the brain parenchyma and the dura. This mimics a situation that is commonly occurring in the clinic. Flow cytometry analysis revealed significant differences in the activation state of metastasis-associated macrophages (MAMs) at the two locations. Concurrently, gene expression analysis identified significant differences in molecular profiles of cancer cells that have metastasized to the brain parenchyma as compared to the dura. This included differences in inflammation-related pathways, NF-kB1 activity and cytokine profiles. The most significantly upregulated cytokine in brain parenchyma- versus dura-derived cancer cells was Lymphotoxin ? and a gain-of-function approach demonstrated a direct involvement of this factor in the M2 polarization of parenchymal MAMs. This established a link between metastatic site-specific properties of cancer cells and the MAM activation state.
| S-EPMC5173073 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-07-25 | GSE249577 | GEO