Effect of CSF1R targeting on human macrophages in normoxia and hypoxia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE263919 | GEO | 2024/04/18
REPOSITORIES: GEO
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Project description:Metastasis is the primary cause of mortality in breast cancer patients. Tumor associated macrophages (TAMs) are active collaborators in mediating several steps of the tumor metastatic cascade, but the molecular details governing this collaboration remain ill-defined. Colony Stimulating Factor 1 (CSF1), a factor critical for macrophage differentiation and survival, functions to recruit TAMs to the primary tumor site, and anti-CSF1 therapies are in clinical trials.In this study, we tested the effect of inhibiting CSF1 signaling in macrophages on gene expression in metastatic tumor cells in mouse models of breast cancer metastasis. Tumor cells were sorted from lung metastases from control and CSF1R inhibitor treated mice. Several pro-tumor processes were significantly affected by CSF1R inhibitor treatment, including angiogenesis and tumor cell proliferation. In addition, a 29 gene signature derived from this data could retrospectively predict survival in a cohort of luminal B breast cancer patients. Collectievly, our results highlight the utility of employing CSF1R inhibitors for the treatment of metastatic breast cancer. GFP tagged MVT1 metastatic mammary tumor cells were injected intravenously into FVB/N mice. Mice were gavaged with the CSF1R inhibitor GW2580 or vehicle starting one week post injection. GFP tagged tumor cells were sorted from metastatic tumor bearing lungs 1 and 2 weeks post injection from 2 vehicle treated mice for each. These are denoted 1_week_WT and 2_week_WT respectively. GFP tagged tumor cells were simultaneously sorted from mice gavaged with GW2580. These samples are denoted 2_week_GW. RNA was extracted and gene expression profiling was performed using the Affymetrix Mouse Genome 430 2.0 Array platform.
2014-03-13 | E-GEOD-55855 | biostudies-arrayexpress
Project description:Metastasis is the primary cause of mortality in breast cancer patients. Tumor associated macrophages (TAMs) are active collaborators in mediating several steps of the tumor metastatic cascade, but the molecular details governing this collaboration remain ill-defined. Colony Stimulating Factor 1 (CSF1), a factor critical for macrophage differentiation and survival, functions to recruit TAMs to the primary tumor site, and anti-CSF1 therapies are in clinical trials.In this study, we tested the effect of inhibiting CSF1 signaling in macrophages on gene expression in metastatic tumor cells in mouse models of breast cancer metastasis. Tumor cells were sorted from lung metastases from control and CSF1R inhibitor treated mice. Several pro-tumor processes were significantly affected by CSF1R inhibitor treatment, including angiogenesis and tumor cell proliferation. In addition, a 29 gene signature derived from this data could retrospectively predict survival in a cohort of luminal B breast cancer patients. Collectievly, our results highlight the utility of employing CSF1R inhibitors for the treatment of metastatic breast cancer.
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Project description:Caspases, which are key effectors of apoptosis, have demonstrated non-apoptotic functions. One of these functions is the differentiation into macrophages of peripheral blood monocytes exposed to Colony-Stimulating Factor-1 (CSF1). Conversely, GM-CSF induces the differentiation of monocytes into macrophages in a caspase-independent manner. Macrophages generated by CSF1 and GM-CSF have distinct polarity. Macrophage polarization plays an important role in the pathogenesis of diverse human diseases as cancer, leading us to explore if caspase inhibition would affect macrophage polarization. To explore the role of caspases in CSF1 differentiation, we used human monocytes sorted from buffy coats treated by cytokines. We reported that caspase inhibition delays the ex vivo differentiation of peripheral blood monocytes exposed to CSF1 and modifies the phenotype of generated macrophages, e.g. cell shape, surface markers. Moreover, by RNAseq, we observed that the macrophages generated in presence of CSF1 and QVD are different from CSF1-treated monocytes and from GM-CSF-treated monocytes. Cell cycle and focal adhesion-related pathway genes were selectively down-regulated. This study confirms the importance of caspase activation in CSF1 differentiation.
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Project description:Caspases, which are key effectors of apoptosis, have demonstrated non-apoptotic functions. One of these functions is the differentiation into macrophages of peripheral blood monocytes exposed to Colony-Stimulating Factor-1 (CSF1). Macrophage polarization plays an important role in the pathogenesis of diverse human diseases as cancer, leading us to explore if caspase inhibition would affect macrophage polarization. To explore the role of caspases in CSF1 differentiation, we used human monocytes sorted from buffy coats treated by cytokines. We reported that caspase inhibition delays the ex vivo differentiation of peripheral blood monocytes exposed to CSF1 and modifies the phenotype of generated macrophages, e.g. cell shape, surface markers. Moreover, by RNAseq, we observed that the macrophages generated in presence of CSF1 and QVD are different from CSF1-treated monocytes. This study confirms the importance of caspase activation in CSF1 differentiation.
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Project description:Colony-stimulating factor 1 receptor (CSF1R) signaling controls MФ differentiation and function, and blocking CSF1R exerts antitumor effects in solid tumors. We examined the effects of CSF1R blockade on multiple therapy. Our results showed that CSF1R blockade inhibited the differentiation, proliferation and survival of M2 and myeloma-associated MФs (MAMs). Microarray was used for determining CS7 effect on polarization of MAMs. We used microarrays to detail the global programme of gene expression underlying polarizaiton of myeloma-associated macrophages by CSF1R antibody treatment and identified distinct classes of polarization-related genes during this process.
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Project description:Mesothelioma arises in humans after prolonged chronic inflammation driven by the presence of inhaled asbestos fibres in the chest cavity. We have generated a genetically engineered mouse model of mesothelioma that combines CRE-mediated deletion of 3 disease-relevant tumour suppressor genes, namely Cdkn2a, Nf2 and p53, with a single intrapleural injection of asbestos. Tumours arising in these mice are heavily infiltrated by macrophages, which play. key roles in tumour development and are thought to create a permissive environment for tumour growth. We used a CSF1R inhibitor, AZD7507, to suppress macrophages, starting from day 60 post tumour initiation. This experiment analysed the overall tumour transcriptome in response to macrophage suppression
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Project description:Chronic graft-versus-host disease (cGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation. Central nervous system (CNS) involvement is becoming increasingly recognised, where brain-infiltrating donor MHC class II+ bone marrow-derived macrophages (BMDM) drive pathology. BMDM are also mediators of cutaneous and pulmonary cGVHD, and clinical trials assessing the efficacy of antibody blockade of colony-stimulating factor 1 receptor (CSF1R) to deplete macrophages are promising. We hypothesised that CSF1R antibody blockade may also be a useful strategy to prevent/treat CNS cGVHD. Increased blood-brain barrier permeability during acute GVHD (aGVHD) facilitated CNS antibody access and microglia depletion by anti-CSF1R treatment. However, CSF1R blockade early post-transplant unexpectedly exacerbated aGVHD neuroinflammation. In established cGVHD, vascular changes and anti-CSF1R efficacy were more limited. Anti-CSF1R-treated mice retained donor BMDM, activated microglia, CD8+ and CD4+ T cells, and local cytokine expression in the brain. These findings were recapitulated in GVHD recipients where CSF1R was conditionally depleted in donor CX3CR1+ BMDM. Notably, inhibition of CSF1R signalling post-transplant failed to reverse GVHD-induced behavioural changes. Moreover, we observed aberrant behaviour in non-GVHD control recipients administered anti-CSF1R blocking antibody and naïve mice lacking CSF1R in CX3CR1+ cells, revealing a novel role for homeostatic microglia and indicating that ongoing clinical trials of CSF1R inhibition should assess neurological adverse events in patients. In contrast, transfer of Ifngr-/- grafts could reduce MHC class II+ BMDM infiltration, resulting in improved neurocognitive function. Our findings highlight unexpected neurological immune toxicity during CSF1R blockade and provide alternative targets for the treatment of cGVHD within the CNS.
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Project description:Microglia are long-lived myeloid cells in the central nervous system that are implicated in many neurological diseases. The differentiation of pluripotent stem cells provides an opportunity to develop in vitro human cellular models carrying disease gene mutations complementing existing animal models of disease. Microglia are particularly sensitive to their cellular environment and can adopt a variety of reactive states depending on different pathological conditions which may be difficult to mimic in vitro. Therefore, to best investigate human microglia in vivo, it would be helpful to generate mice whose endogenous microglia are exchanged with human cells without the need of genetic manipulation of donor cells which could alter microglia function. Colony stimulating factor 1 receptor (CSF1R) signaling is critical for microglial survival in mice, and humans with CSF1R mutations are born with fewer microglia. We made the surprising discovery that transplanted human pluripotent stem cell-derived microglia (hMG) survive pharmacological CSF1R inhibition unlike endogenous mouse microglia. Cellular assays confirmed that CSF1R signaling is necessary for human microglia survival and revealed differential CSF1R signaling with species-specific ligands. Moreover, receptor ligands and small molecule inhibitors acted in a competitive fashion. Based on these insights, we found that transient CSF1R inhibition after cell transplantation led to near-complete and wide-spread repopulation of hMGs into the mouse brain of immunodeficient mice with humanized CSF1 ligand. This approach allows the facile generation of mice whose brain microglia are replaced with genetically unmodified human cells.
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Project description:The role of tissue resident macrophages during tissue regeneration or fibrosis is not well-understood, mainly due to the lack of a specific marker for their identification. Here, we identified two populations of skeletal muscle resident macrophages: TIM4- macrophages which are replenished from the blood and LYVE1+TIM4+ macrophages that locally self-renew (self-renewing resident macrophages, SRRMs). Using a CSF1R inhibition/withdrawal approach to specifically deplete SRRMs, we found that they provide a non-redundant function in clearing damage-induced apoptotic cells early after extensive acute injury. In contrast, in chronic mild injury as seen in a mouse model of Duchenne muscular dystrophy, we showed that depletion of both resident populations through long term CSF1R inhibition changes muscle fiber composition from damage-sensitive glycolytic fibers towards damage-resistant glycolytic-oxidative fibers protecting muscle against contraction induced injury. This later finding reveals a new role for resident macrophages in modulating tissue metabolism and has therapeutic potential in light of the ongoing clinical testing of CSF1R inhibitors.
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