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A macrophage autonomous alpha4beta1integrin-Syk-Rac2 signaling axis controls macrophage differentiation, tumor growth and metastasis

ABSTRACT: Macrophages, play an essential role in promoting tumor growth by affecting angiogenesis, immune suppression, invasion and metastasis. The signal transduction events within macrophages which encode the complex cascade of events required for tumor growth and polarization of macrophages are poorly understood. We have discovered an ECM dependent signaling pathway in macrophages that regulates M2 macrophage differentiation, tumor growth, invasion and metastasis. We provide direct evidence that a macrophage autonomous, α4β1 integrin dependent Syk-Rac2 signaling axis acts in concert with the p110 isoform (PTEN-PI-3 kinase pathway) to control metastasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE41236 | GEO | 2012/10/02

SECONDARY ACCESSION(S): PRJNA176342

REPOSITORIES: GEO

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A macrophage autonomous alpha4beta1integrin-Syk-Rac2 signaling axis controls macrophage differentiation, tumor growth and metastasis

Project description:Macrophages, play an essential role in promoting tumor growth by affecting angiogenesis, immune suppression, invasion and metastasis. The signal transduction events within macrophages which encode the complex cascade of events required for tumor growth and polarization of macrophages are poorly understood. We have discovered an ECM dependent signaling pathway in macrophages that regulates M2 macrophage differentiation, tumor growth, invasion and metastasis. We provide direct evidence that a macrophage autonomous, M-NM-14M-NM-21 integrin dependent Syk-Rac2 signaling axis acts in concert with the p110 isoform (PTEN-PI-3 kinase pathway) to control metastasis. Bone marrow derived macrophages from five wild type and five Rac2 -/- mutant C57BL mice.

2012-10-02 | E-GEOD-41236 | biostudies-arrayexpress

A macrophage autonomous Î±4Î²1integrin-Syk-Rac2 signaling axis controls macrophage differentiation, tumor growth and metastasis

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2012-11-15 | E-GEOD-41717 | biostudies-arrayexpress

A macrophage autonomous α4β1integrin-Syk-Rac2 signaling axis controls macrophage differentiation, tumor growth and metastasis

Project description:Macrophages, play an essential role in promoting tumor growth by affecting angiogenesis, immune suppression, invasion and metastasis. The signal transduction events within macrophages which encode the complex cascade of events required for tumor growth and polarization of macrophages are poorly understood. We have discovered an ECM dependent signaling pathway in macrophages that regulates M2 macrophage differentiation, tumor growth, invasion and metastasis. We provide direct evidence that a macrophage autonomous, α4β1 integrin dependent Syk-Rac2 signaling axis acts in concert with the p110 isoform (PTEN-PI-3 kinase pathway) to control metastasis.

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Epidermal growth factor shedding directs macrophage education in cancer

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.

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Branched-chain ketoacids derived from cancer cells modulate macrophage polarization and metabolic reprogramming

Project description:<p>Macrophages are prominent immune cells in the tumor microenvironment that can be educated into pro-tumoral phenotype by tumor cells to favor tumor growth and metastasis. The mechanisms that mediate a mutualistic relationship between tumor cells and macrophages remain poorly characterized. Here, we have shown <em>in vitro</em> that different human and murine cancer cell lines release branched‐chain α‐ketoacids (BCKAs) into the extracellular milieu, which influence macrophage polarization in an monocarboxylate transporter 1 (MCT1)‐dependent manner. We found that α‐ketoisocaproate (KIC) and α‐keto‐β‐methylvalerate (KMV) induced a pro‐tumoral macrophage state, whereas α‐ketoisovalerate (KIV) exerted a pro‐inflammatory effect on macrophages. This process was further investigated by a combined metabolomics/proteomics platform. KMV and KIC altered macrophage tricarboxylic acid (TCA) cycle intermediates and increased polyamine metabolism. Proteomic and pathway analyses revealed that the three BCKAs, especially KMV, exhibited divergent effects on the inflammatory signal pathways, phagocytosis, apoptosis and redox balance. These findings uncover cancer‐derived BCKAs as novel determinants for macrophage polarization with potential to be selectively exploited for optimizing antitumor immune responses.</p>

2022-10-03 | MTBLS4497 | MetaboLights

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Project description:Macrophages are very plastic and play key roles in maintenance of tissue homeostasis. In cancer progression, macrophages also take parts through all the processes, from the initiation, progression, to the final tumor metastasis. Although energy deprivation and autophagy are widely used for cancer therapy, most of these strategies are not meant to target macrophages resulting in undesired effects and unsatisfactory outcomes for cancer immunotherapy. Herein, we developed a lanthanum nickel oxide (LNO) nanozyme that possesses phosphatase-like activity for ATP hydrolysis. Meanwhile, the autophagy of macrophages induced by LNO promotes the polarization of macrophages from M2-like macrophage (M2) to M1-like macrophage (M1) and reduces tumor-associated macrophages in tumor-bearing mice, exhibiting capability of killing tumor-associated macrophage and anti-tumor effect in vivo. Furthermore, pre-coating by myeloid cell membrane on the surface of LNO significantly enhanced antitumor immunity. Our findings demonstrate that phosphatase-like nanozyme, LNO can specifically induce macrophage autophagy that improves therapeutic efficacy and offers valuable strategies for cancer immunotherapy.

2024-08-10 | PXD051695 | Pride

Mus musculus

Project description:A macrophage autonomous alpha4beta1integrin-Syk-Rac2 signaling axis controls macrophage differentiation, tumor growth and metastasis

| PRJNA176342 | ENA

Mus musculus

Project description:A macrophage autonomous α4β1integrin-Syk-Rac2 signaling axis controls macrophage differentiation, tumor growth and metastasis

| PRJNA178015 | ENA

Scavenger Receptor A1 Prevents Non-Small Cell Lung Cancer Metastasis by Suppressing Macrophage Serum Amyloid A1 Expression

Project description:Metastasis is the key determinant of poor prognosis for advanced-stage NSCLC patients. Although an important contributor to metastasis is cross-talk between tumor-associated macrophages (TAMs) and tumor cells, its regulation is not fully understood. Expressed primarily in macrophages, scavenger receptor A1 (SR-A1) has been associated with lung tumorigenesis. Here, the mechanistic basis for the involvement of SR-A1 in lung cancer prognosis was investigated using population genetics, transcriptomics, and functional analyses. SR-A1 genetic variants were investigated for possible association with survival of advanced-stage NSCLC patients in the Harvard Lung Cancer Study cohort. Two SNPs (rs17484273, rs1484751) in SR-A1 were significantly associated with poor overall survival of NSCLC patients. Further, data from The Cancer Genome Atlas showed a considerable down-regulation of SR-A1 in lung tumor tissues. The association of SR-A1 with prognosis was validated in animal models in the context of lung cancer metastasis. Macrophages derived from SR-A1 knockout mice accelerated metastasis in a lung cancer mouse model. On the other hand, tumor cell seeding, migration, and invasion as well as macrophage accumulation in lung cancer tissue were enhanced in SR-A1 knockout mice. Furthermore, SR-A1 deficiency promoted up-regulation of serum amyloid A1 (SAA1) in macrophages, which appeared to be mediated by MAPK/Ikappa-B/NF-kappaB signaling. Further, SAA1 exposure promoted tumor cell invasion and macrophage migration in vitro and in vivo, but these effects were blocked by administration of an anti-SAA1 antibody. These findings suggest that SR-A1 may suppress lung cancer metastasis by down-regulating SAA1 production in macrophages.

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A conserved atypical MFS family member orchestrates a subset of O-glycosylation to facilitate macrophage dissemination and tissue invasion

Project description:Aberrant display of the truncated core1 O-glycan T-antigen is a common feature of human cancer cells that correlates with metastasis. Here we show that T-antigen in Drosophila melanogaster macrophages is involved in their developmentally programmed tissue invasion. Higher macrophage T-antigen levels require an atypical major facilitator superfamily (MFS) member that we named Minerva which enables macrophage dissemination and invasion. We characterize for the first time the T and Tn glycoform O-glycoproteome of the Drosophila melanogaster embryo, and determine that Minerva increases the presence of T-antigen on protein pathways previously linked to cancer, most strongly on the protein sulfhydryl oxidase Qsox1 which we show is required for macrophage invasion. Minerva’s vertebrate ortholog, MFSD1, rescues the minerva mutant’s migration and T-antigen glycosylation defects. We thus identify a key conserved regulator that orchestrates O-glycosylation on a protein subset to activate a program governing migration steps important for both development and cancer metastasis

2019-04-01 | PXD011045 | Pride

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