Spon1+ inflammatory monocytes promote collagen remodeling and lung cancer metastasis through lipoprotein receptor 8 signaling.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1081940 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Lung cancer is the leading cause of cancer-related deaths in the world, and non-small cell lung cancer (NSCLC) is the most common subset. Although immune checkpoint inhibitors have improved outcomes in a subset of NSCLC patients, these effects are usually not durable. Thus, a more complete understanding of how immune niches within the tumor microenvironment (TME) promote NSCLC progression will allow us to build upon these advances. We previously found that infiltration of tumor inflammatory monocytes (TIMs) into lung squamous carcinoma (LUSC) tumors is associated with increased metastases and poor survival. To further understand how TIMs promote metastases, we compared RNA-seq profiles of TIMs from several LUSC metastatic models with IMs of non-tumor bearing controls. We identified Spon1, a secreted extracellular matrix glycoprotein, as upregulated in TIMs and that Spon1 expression in LUSC tumors corresponds with poor survival. Bioinformatic analyses of the Cancer Genome Atlas (TCGA) revealed that LUSC tumors with high SPON1 expression significantly enriched for collagen extracellular matrix (ECM) signatures. Unexpectedly, we observed SPON1+ TIMs mediate their effects directly through LRP8 (ApoER2) on NSCLC cells, which results in TGFβ1 activation and robust production of fibrillar collagens. Using several orthogonal approaches, we demonstrate that SPON1+ TIMs are sufficient to promote NSCLC metastases. Additionally, we find that Spon1 loss in the host, or Lrp8 loss in cancer cells, results in a significant decrease of both high-density collagen matrices and metastases. Finally, we confirm the relevance of the SPON1/LRP8/TGFβ1 axis with collagen production and survival in NSCLC patients. Taken together, our study describes how SPON1+ TIMs promotes collagen remodeling and NSCLC metastases through an LRP8-TGFβ1 signaling axis in lung cancer cells.
2024-03-05 | GSE260524 | GEO
Project description:stimulation of whole blood using 5 ng/ml lipopolysaccharide (LPS, gram -ve bacterial endotoxin) or 5 ug/ml CRP-18 (collagen-related peptide; GPO-18). Monocytes respond to stimuli differently. This experiment was designed to elucidate the transcriptional differences in monocytes responding to either a danger signal (supplied by LPS) or a damage signal (supplied by CRP-18). CRP-18 is a collagen mimetic and was used to represent collagen exposure at sites of vessel damage. Exposed collagen activates platelts which in turn activate monocytes. The transcriptional differences which ensue are not known yet and were investigated in this work.
2010-01-01 | E-TABM-483 | biostudies-arrayexpress
Project description:Physiologic turnover of interstitial collagen is mediated by a sequential pathway, in which collagen is fragmented by pericellular collagenases, endocytosed by specific collagen receptors, and routed to lysosomes for degradation by lysosomal cathepsins. Here, we used intravital microscopy to investigate if malignant tumors, which are characterized by high rates of extracellular matrix turnover, utilize a similar collagen degradation pathway. Tumors of epithelial, mesenchymal, or neural crest origin all displayed vigorous endocytic collagen degradation with an abundance of cells engaged in this process. These cells were identified as tumor-associated macrophage (TAM)-like cells that degraded collagen in a mannose receptor-dependent manner. Accordingly, increased intra-tumoral collagen was observed in mannose receptor-deficient mice. Whole transcriptome profiling uncovered a distinct extracellular matrix-catabolic signature of these collagen-degrading TAMs. Lineage-ablation studies revealed that collagen-degrading TAMs originated from circulating CCR2+ monocytes. The study identifies a novel function of TAMs in altering the tumor microenvironment through endocytic collagen turnover and establishes macrophages as centrally engaged in tumor-associated collagen degradation.
2018-01-01 | GSE107053 | GEO
Project description:Extracellular matrix (ECM) structural and compositional abnormalities are a hallmark of many cancers. Tumor associated macrophages (TAM) are considered pivotal players in mounting pro-tumoral functions; yet, their role in tumor-ECM remodeling remains largely ambiguous. Using an orthotopic murine model of colorectal cancer we defined two major CRC TAM subsets arising from Ly6Chi monocytes recruited in a CCR2-depedent manner. TAM-deficient CRC tumors established Ccr2-/- mice exhibited attenuated growth. Advanced imaging techniques revealed that the enhanced deposition, linearization and cross-linking of collagen fibers typical to tumor growth were absent in the Ccr2-/- tumors. Moreover, the Ccr2-/- tumors displayed altered ECM composition with 348 proteins that were differentially expressed in comparison with WT tumors, among them 46 were ECM related. Integrating transcriptomic and proteomic approaches we defined a TAM signature of ECM remodeling enzymes, structural and affiliated proteins. Specifically, were prominent proteins involved with the synthesis and assembly of collagen type I, IV and XIV. Finally, decellularized 3D ECM fragments extracted from WT tumors, but not from Ccr2-/- tumors or upstream healthy colon, enhanced tumor cell proliferation in vitro and tumor development in the native colonic environment. Collectively, our integrated biophysical-immunologic-omic approaches uncover new mechanistic insights of TAM-mediated remodeling of tumor ECM structure and composition.
2016-09-26 | PXD002094 | Pride
Project description:Monocytes and monocyte-derived macrophages are myeloid cells that span all tissues and play pivotal roles in tissue homeostasis and tumor progression. Here, we show that these cells express high levels of leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), a known receptor for Collagen. We hypothesized that LAIR1 mediates the interaction between myeloid cells and the collagen-rich extracellular matrix (ECM). First, using a high throughput cell-based platform for membrane protein interactome discovery, we identified Colec12, a protein expressed by non-hematopoietic stromal cells, as a novel high affinity LAIR1 ligand. Global phosphoproteomics was employed to determine the signaling pathways triggered upon LAIR1 engagement by Colec12 and Collagen in monocytes, which suggested a main role in cell survival and cell cycle regulation. Using a combination of genomic, phenotypic and transcriptomics assays, we corroborated the homeostatic role of LAIR1 signaling in mice. Under homeostatic conditions, LAIR1 preferentially restrained proliferation and promoted survival of non-classical monocytes and dysregulation of this pathway led to an increase in classical monocytes and tissue-infiltrating macrophages in lungs. In tumors, LAIR1 deficiency in myeloid cells exacerbated metastasis to lungs in mice. Finally, we confirmed LAIR1 and LAIR1-expressing myeloid cell signatures as positive prognostic factors in human metastatic melanoma. Collectively, our study shows that ECM provides monocytes and monocyte-derived macrophages with important homeostatic signals that are mediated via the immunoreceptor LAIR1. This work illuminates new aspects of ECM-myeloid cell interactions that may be pertinent in cancer, fibrotic diseases and therapeutic development.
2021-05-03 | MSV000087357 | MassIVE
Project description:We previously found that a native lipoprotein mix with a high VLDL+LDL/HDL ratio causes a global de novoDNA methylation in THP-1 macrophages. In the present experiment we assessed the consequences of global lipoprotein-induced de novo DNA methylation on global gene expression in the same cells. Moreover, we sought to use gene expression array data to measure RNA expression levels for candidate factors mediating the epigenetic effects of lipoproteins. Experiment Overall Design: Human native VLDL, LDL and HDL lipoproteins were isolated from buffy coats, fractionated by ultracentrifugation, stored at -80deg., desalted to PBS before usage and kept at 4deg. for a maximum of 7d. THP-1 monocytes were differentiated to macrophages, stimulated for 24h with a mix of 68.8mg/ml VLDL, 32.1mg/ml LDL, 91.1mg/ml HDL or unstimulated (control), in serum-free medium with 2% BSA. Three independently isolated lipoprotein samples were used in triplicate.
2008-06-16 | E-GEOD-9101 | biostudies-arrayexpress
Project description:Ly6Chi monocytes massively infiltrate the CRC-tumors by virtue of their CCR2 expression and further mature into Ly6CloF4/80hi CD64hiMHCII+ TAM upon tumor progression. We demonstrated that TAM-deficient tumors display impaired tumor-growth via alternation of the ECM morphology, structure and composition. Using advanced high-resolution optical imaging to visualize the tumoral-ECM macromolecule network together with transcriptomic and proteomic approaches we unraveled that TAM play critical role in the deposition, linearization and cross-linking of collagenous ECM. Remarkably, we show that cues embedded in ECM by TAM-mediated remodeling activity promote tumor cell proliferation in vitro and orthotopic tumor development in vivo. Abnormal remodeling of the extracellular matrix (ECM) structural and compositional is a hallmark of many cancers. While tumor associated macrophages (TAM) are considered pivotal players in mounting pro-tumoral functions, their role in tumor-ECM remodeling remains largely ambiguous. We found that TAM-deficient CRC tumors established in Ccr2-/- mice exhibited attenuated growth. Advanced molecular imaging revealed that the enhanced deposition, linearization and cross-linking of collagen fibers typical to tumor growth were absent in the Ccr2-/- tumors. Integrating transcriptomic and proteomic approaches we defined a TAM signature of ECM remodeling enzymes, structural and affiliated proteins involved with the synthesis and assembly of collagen. The Ccr2-/- tumors displayed altered ECM composition with 348 proteins that were differentially expressed in comparison with WT tumors, among them 46 were ECM related. Decellularized 3D ECM fragments extracted from WT tumors, but not from Ccr2-/- tumors or upstream healthy colon, enhanced tumor cell proliferation in vitro and tumor development in the native colonic environment indicating that TAM have a critical role in priming pathological ECM cues.
2016-09-15 | GSE67953 | GEO
Project description:Mmp14-Dependent Remodeling of the Pericellular-Dermal Collagen Interface Governs Fibroblast Survival
| PRJNA1108711 | ENA
Project description:Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components. In this study we apply RNA-seq analysis to healthy human monocytes exposed to oxidized Low Density Lipoprotein (oxLDL), in vitro.
2019-11-07 | GSE122267 | GEO
Project description:Transcriptional remodeling of primary human monocytes exposed to Leishmania braziliensis
| PRJNA869562 | ENA