Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA377074 | ENA |
REPOSITORIES: ENA
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Project description:Tumor-associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment convey distinct sensitivities to TAM targeting.We generated syngeneic PDGFB-driven and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth. We also investigated the co-targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in tumor microenvironment cellular compositions and functions in PDGFB- and RAS-driven gliomas. We found that growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-tumor microglia, whereas TAMs in mesenchymal RAS-driven GBM were enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and changed the morphology of RAS-driven gliomas.Our work identify functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-angiogenic therapy and CSF1R inhibition. These data highlight the importance of characterization of the microenvironment landscape in order to optimally stratify patients for TAM-targeted therapy.
2021-10-08 | GSE185420 | GEO
Project description:In order to assess whether differences in the transcriptomic profile of human tumor-associated macrophages vs. alveolar macrophages from adjacent non-tumor-tissue (GSE162669) were caused by factors secreted by tumor cells, primary human monocyte-derived macrophages (MDMs) were polarized towards a TAM-like phenotype by cultivating them in tumor cell-conditioned medium. A genome-wide comparison by bulk RNA-Seq confirmed a high similarity of ex vivo TAMs and in vitro polarized TAM-like macrophages. Other polarization schemes (M1: LPS/IFN-gamma, M2: IL10 or IL4) did not lead to similar transcriptomic changes. For details, see Hoppstädter et al., 2021 (doi:10.1016/j.ebiom.2021.103578).
2021-09-25 | GSE162698 | GEO
Project description:The study of the roles of macrophages in the microenvironment of cancer cells (tumor-associated macrophages, TAM) has gained deep insight over the recent years. Here, we describe gene expression profile of chronic lymphocytic leukemia (CLL)-associated macrophages, also called nurse-like cells (NLC), derived from in vitro co-cultures system. We define these NLC as M2-oriented, TAM-like specific subset of macrophages, with very few inter-individual variations in gene expression profiles. CLL patients PBMC were isolated and cultured for 15 days in vitro. NLC were then isolated, mRNA were purified and hybridized on Affymetrix U133 plus 2.0 chips. Data were normalized by RMA5
2012-12-11 | E-GEOD-42733 | biostudies-arrayexpress
Project description:Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAM) are often associated with poor prognosis in cancer. In order to better understand the influence of tumor cell apoptosis and in particular its effect on TAM, we investigated global gene expression signatures of undisturbed TAM engaged in engulfment of apoptotic tumor cells. We studied a xenograft model of an aggressive ‘starry-sky’ non-Hodgkin’s lymphoma, Burkitt’s lymphoma (BL), in which apoptotic tumor cells are common and frequently observed in association with the starry-sky TAM (SS-TAM, so called because they appear histologically as ‘stars’ in a ‘sky’ of tumor cells) that accumulate in these tumors. We used a BL cell line (BL2) whose cells phenotypically resemble the tumor biopsy cells from which the line was derived including the capacity to undergo apoptosis constitutively. BL xenografts in SCID mice closely recapitulated the starry-sky histological picture of the human lymphoma. Due to the high sensitivity of macrophages to their environments, we adopted laser-capture microdissection of individual SS-TAM in BL xenografts in order to obtain unbiased in situ transcriptional profiles of these cells, which we compared specifically with those of similarly-captured macrophages, the tingible-body macrophages from normal germinal centers (GCM). The rationale for this comparison was based upon BL being a germinal center malignancy and tingible-body macrophages being regarded as normal equivalents of SS-TAM. Gene expression profiles of SS-TAM from BL2 xenograft tumors were compared to splenic GCM profiles. Three mice from each group were analysed. RNA was isolated from 1000 captured macrophages from each mouse and global gene expression signatures were obtained using Affymetrix Mouse Gene 1.0 GeneChip arrays.
2014-12-20 | E-GEOD-64366 | biostudies-arrayexpress
Project description:In the comparison between TAM-treated BIK-suppressed MCF7 cells vs. MCF.7 treated with TAM, we found some genes which have been associated with drug resistance.
2014-08-28 | GSE60802 | GEO
Project description:C57BL6 mice were subjected to a controlled cortical impact (CCI) to induce a unilateral traumatic brain injury (TBI). After surgery, mice were treated for 5 days with the CSF1R antagonist, PLX3397 or vehicle by daily i.p. injections. PLX3397 is an inhibitor of Colony Stimulating Factor receptor 1 (CSF1R) that leads to a depletion of microglial cells which was confirmed by immunohistochemistry in a subgroup of mice at day 5. Termination of PLX3397 allows for a repopulation of microglial cells which was near complete at 30 days, as assessed by immunofluorescence studies. Perilesional cortical tissue was obtained at the late time point of 30 days after TBI to assess lasting effects of microglia depletion for cortical reorganization that manifested at the transcriptional level. The RNAseq study was done in male and female mice (PLX3397 n = 5 male, 5 female; vehicle n = 5 male, 5 female). Behavioral scores for well-being and motor functions were obatined repeatedly during the observation time. Histology of brain lesion size, indices of neuronal damage and neuroinflammation were obtained at 5d and 30d after TBI. Microglia depletion (PLX3397 treatment) did not reduce the lesion volume and hindered phagocytosis and removal of the hematoma at 5 days, but reduced structural brain damage and neuron loss at 30 days after the injury. Neuroinflammatory markers tended to be lower in PLX3397 treated male than female mice which was associated with better neurological outcome. Overall, CSF1R inhibition provided only subtle lasting beneficial effects.
2022-12-28 | GSE196121 | GEO
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:microRNA expression during tumor-associated macrophage (TAM) differentiation
| PRJNA279841 | ENA
Project description:The 18 kDa translocator protein (TSPO) emerges as an important PET biomarker to assess the tumor microenvironment (TME) in glioblastoma. However, various cellular sources hamper interpretation and biological understanding of TSPO and other immune biomarkers in the TME. Thus, we established a novel method, combining immunomagnetic cell sorting after radiotracer injection (scRadiotracing) with 3D histology via light sheet microscopy and proteomics to dissect cellular allocation of TSPO enrichment in glioblastoma. Single tumor cells of implanted SB28 glioblastoma mice indicated 1.37-fold higher TSPO tracer uptake and 1.46-fold higher TSPO protein expression levels when compared to tumor associated microglia/macrophages (TAMs). Using proteomics, we compared the proteome of tumor associated microglia/macrophages (TAMs), Tumor tissue (TT) and control microglia from WT mice without glioblastoma. This analysis identified TAM specific targets for PET radioligand development with additional potential to monitor diverse TAM subpopulations in vivo. In summary, our data indicate that tumor cells need to be acknowledged as the main contributor to TSPO as a biomarker in glioblastoma. Combining cellular tracer uptake measures with 3D histology facilitates precise allocation of complex PET signal sources and will serve to validate novel TAM specific radioligands.
2023-10-30 | PXD044033 | Pride
Project description:Profiling of tumor-associated macrophages (TAM) after anti-MerTK treatment
| PRJNA490763 | ENA