Re-education of tumor-associated macrophages by CXCR2 blockade drives senescence and tumor inhibition in advanced prostate cancer
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ABSTRACT:
PROVIDER: PRJNA510636 | ENA |
REPOSITORIES: ENA
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Project description:Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment that supports tumorigenesis. Here we found that prostate tumors are strongly infiltrated by TAMs expressing the C-X-C chemokine receptor type 2 (CXCR2). Pharmacological blockade of the CXCR2 receptor by a selective antagonist promoted the re-education of TAMs towards a pro-inflammatory phenotype. In vitro gene expression profiling revealed that CXCL2 promotes a pro-tumorigenic (M2-like) functional state in macrophages.
2019-06-03 | GSE125273 | GEO
Project description:Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment that supports tumorigenesis. Here we found that prostate tumors are strongly infiltrated by TAMs expressing the C-X-C chemokine receptor type 2 (CXCR2). Pharmacological blockade of the CXCR2 receptor by a selective antagonist promoted the re-education of TAMs towards a pro-inflammatory phenotype. Strikingly, CXCR2 knockout monocytes infused in Ptenpc-/-; Trp53pc-/- mice preferentially differentiatied in TNFα-releasing pro-inflammatory macrophages leading to senescence induction and tumor inhibition. Moreover, tumor cells harboring PTEN deletion were more sensitive to TNFα-induced senescence, when compared to PTEN WT tumors, due to increased levels of TNFR1. Our results identify TAMs as a target in prostate cancer therapy and describe a novel therapeutic strategy based on CXCR2 blockade to harness the anti-tumorigenic potential of macrophages against this disease.
2019-12-10 | GSE124058 | GEO
Project description:Re-education of tumor-associated macrophages by CXCR2 blockade drives senescence and tumor inhibition in advanced prostate cancer
| PRJNA515730 | ENA
Project description:Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment supporting tumorigenesis. TAMs re-education has been proposed as a strategy to promote tumor inhibition. However, whether this approach may work in prostate cancer is unknown. Here we find that Pten-null prostate tumors are strongly infiltrated by TAMs expressing C-X-C chemokine receptor type 2 (CXCR2), and activation of this receptor through CXCL2 polarizes macrophages toward an anti-inflammatory phenotype. Notably, pharmacological blockade of CXCR2 receptor by a selective antagonist promoted the re-education of TAMs toward a pro-inflammatory phenotype. Strikingly, CXCR2 knockout monocytes infused in Ptenpc-/-; Trp53pc-/- mice differentiated in tumor necrosis factor alpha (TNF-?)-releasing pro-inflammatory macrophages, leading to senescence and tumor inhibition. Mechanistically, PTEN-deficient tumor cells are vulnerable to TNF-?-induced senescence, because of an increase of TNFR1. Our results identify TAMs as targets in prostate cancer and describe a therapeutic strategy based on CXCR2 blockade to harness anti-tumorigenic potential of macrophages against this disease.
| S-EPMC6715643 | biostudies-literature
Project description:Epithelial ovarian cancer (EOC) is one of the most lethal gynecological cancers worldwide. EOC cells educate tumor-associated macrophages (TAMs) through CD44-mediated cholesterol depletion to generate an immunosuppressive tumor microenvironment (TME). In addition, tumor cells frequently activate Notch1 receptors on endothelial cells (ECs) to facilitate metastasis. However, little is known whether the endothelium would also influence the education of recruited monocytes. Here, we report that canonical Notch signaling through RBPJ in ECs is an important player in the education of TAMs and EOC progression. Deletion of Rbpj in the endothelium of adult mice reduced infiltration of monocyte-derived macrophages into the TME of EOC and prevented the acquisition of a typical TAM gene signature. This was associated with stronger cytotoxic activity of T cells and decreased tumor burden. Mechanistically, we identified CXCL2 as a novel Notch/RBPJ target gene. This angiocrine factor regulates the expression of CD44 on monocytes and subsequent cholesterol depletion of TAMs. Bioinformatic analysis of ovarian cancer patient data showed that increased CXCL2 expression is accompanied by higher expression of CD44 and TAM education. As such, EOC cells employ the tumor endothelium to secrete CXCL2 in order to facilitate an immunosuppressive microenvironment.
2022-09-15 | GSE213371 | GEO
Project description:The development of therapy resistance is inevitable in prostate cancer (PCa) despite maximal inhibition of androgen receptor (AR) signaling. Here, we for the first time purified a rare AR-negative NE-cell subset from primary fresh human PCa tissue based on cell-surface receptor CXCR2 and showed that they possess gene signatures of lethal cancer through transcriptional profiling. Functional studies demonstrate CXCR2 to be a driver of NE cells’ key phenotypes, including loss of AR expression, lineage plasticity, and resistance to hormonal-therapy. Furthermore, CXCR2-driven NE cells are critical for the tumor microenvironment by providing a survival niche for the bulk AR+ luminal cells. Importantly, inhibition of CXCR2 by a chemical inhibitor or genetic manipulation dramatically inhibits aggressive PCa cells in-vitro and in-vivo, demonstrating a central role of NE cells in human PCa. Therefore, we firmly established that targeting NE cells through CXCR2 represents a novel, AR-independent therapeutic strategy that will eliminate all tumor cells (NE and luminal), achieving superior therapeutic efficacy.
2019-12-03 | GSE114326 | GEO
Project description:It is now well-accepted that cancers co-opt the microenvironment to support their growth. However, the molecular mechanisms underlying cancer-microenvironment interactions remain poorly defined. We have found that Rho-associated kinase (ROCK) activity in the epithelial component of mammary tumors selectively actuates Protein kinase R-like endoplasmic reticulum kinase (Perk), causing the recruitment and persistent education of tumor-promoting cancer-associated fibroblasts (CAFs), a key component of the cancer microenvironment. Analysis of tumors from mice and human patients identified Cysteine-rich with EGF-like domains 2 (CRELD2), as the paracrine factor underlying PERK-mediated CAF-education downstream of ROCK. CRELD2 expression was found to be regulated by ATF4 downstream of the PERK pathway and knock-down of CRELD2 prevented tumor progression, demonstrating that the paracrine ROCK-PERK-ATF4-CRELD2 axis is a promoter of breast cancer progression and suggesting new therapeutic opportunities.
2020-05-27 | PXD018253 | Pride
Project description:Tumor Associated Macrophages (TAMs) are known to release cytokines/chemokines that promote tumor survival and angiogenesis. Little is known, however, about their ability to present tumor antigens to CD4 T cells, nor whether such presentation might switch their tumor supporting function. Here we show that TAMs present tumor antigens to CD4 T cells and that upon antigen recognition, the T cells re-educate the TAMs to produce lower amounts of tumor nurturing proteins and greater amounts of anti-angiogenic proteins. The CD4-educated-TAMs display a gene signature characterized by upregulation of INFgamma esponsive genes that have anti-viral and anti-bacterial function. This phenotypic switch is INF-gamma dependent, and necessary for CD4-mediated tumor rejection. CD4-based immunotherapies could take advantage of this re-education process to improve cancer treatment.
2022-08-03 | GSE40920 | GEO
Project description:Macrophages in the tumor microenvironment have a significant impact on tumor progression. Depending on the signaling environment in the tumor, macrophages can either support or constrain tumor growth and metastasis. It is therefore of therapeutic interest to identify the tumor-derived factors that control macrophage education. With this aim, we correlated the expression of ADAM proteases, which are key mediators of cell-cell signaling, to the expression of pro-tumorigenic macrophage markers in human cancer cohorts. We identified ADAM17, a sheddase upregulated in many cancer types, as a protein of interest. Depletion of ADAM17 in cancer cell lines reduced the expression of several pro-tumorigenic markers in neighboring macrophages in vitro as well as in mouse tumor models. Accordingly, ADAM17-/- educated macrophages demonstrated a reduced ability to induce cancer cell invasion. Using quantitative mass spectrometry-based proteomics, we identified HB-EGF, shed by ADAM17 in the cancer cells, as the implicated molecular mediator of macrophage education. Additionally, RNA-seq and ELISA experiments revealed that ADAM17-dependent HB-EGF release induces the expression and secretion of CXCL chemokines in macrophages, which in turn stimulates cancer cell invasion. In conclusion, we provide evidence that ADAM17 mediates a paracrine HB-EGF-chemokine feedback loop, whereby cancer cells hijack macrophages to promote tumor progression.
2022-09-18 | PXD030740 | Pride
Project description:Purpose: CXCR2 was transfected into 32D clone 3 cells simulating the granulocyte and macrophage progenitor cells(GMPs) to confirm the role of CXCR2 in the differentiation of GMPs to macrophage and dendritic cell progenitor cells
2019-08-21 | GSE125347 | GEO