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Science (New York, N.Y.) Aug 2023Tumor microenvironments (TMEs) influence cancer progression but are complex and often differ between patients. Considering that microenvironment variations may reveal...
Tumor microenvironments (TMEs) influence cancer progression but are complex and often differ between patients. Considering that microenvironment variations may reveal rules governing intratumoral cellular programs and disease outcome, we focused on tumor-to-tumor variation to examine 52 head and neck squamous cell carcinomas. We found that macrophage polarity-defined by and (CS) expression but not by conventional M1 and M2 markers-had a noticeably strong prognostic association. CS macrophage polarity also identified a highly coordinated network of either pro- or antitumor variables, which involved each tumor-associated cell type and was spatially organized. We extended these findings to other cancer indications. Overall, these results suggest that, despite their complexity, TMEs coordinate coherent responses that control human cancers and for which CS macrophage polarity is a relevant yet simple variable.
Topics: Humans; Chemokine CXCL9; Head and Neck Neoplasms; Macrophages; Osteopontin; Prognosis; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment; Cell Polarity
PubMed: 37535729
DOI: 10.1126/science.ade2292 -
Science (New York, N.Y.) Jul 2023Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure. We deciphered how immune and stromal cells contribute to atrial fibrillation....
Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure. We deciphered how immune and stromal cells contribute to atrial fibrillation. Single-cell transcriptomes from human atria documented inflammatory monocyte and macrophage expansion in atrial fibrillation. Combining hypertension, obesity, and mitral valve regurgitation (HOMER) in mice elicited enlarged, fibrosed, and fibrillation-prone atria. Single-cell transcriptomes from HOMER mouse atria recapitulated cell composition and transcriptome changes observed in patients. Inhibiting monocyte migration reduced arrhythmia in HOMER mice. Cell-cell interaction analysis identified SPP1 as a pleiotropic signal that promotes atrial fibrillation through cross-talk with local immune and stromal cells. Deleting reduced atrial fibrillation in HOMER mice. These results identify SPP1 macrophages as targets for immunotherapy in atrial fibrillation.
Topics: Animals; Humans; Mice; Atrial Fibrillation; Heart Atria; Macrophages; Mitral Valve Insufficiency; Osteopontin; Gene Deletion; Cell Movement; Single-Cell Gene Expression Analysis
PubMed: 37440641
DOI: 10.1126/science.abq3061 -
Gastroenterology Jul 2023Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning degeneration, and fibrosis, all of which increase the risk...
BACKGROUND & AIMS
Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning degeneration, and fibrosis, all of which increase the risk of progression to end-stage liver disease. Osteopontin (OPN, SPP1) plays an important role in macrophage (MF) biology, but whether MF-derived OPN affects NASH progression is unknown.
METHODS
We analyzed publicly available transcriptomic datasets from patients with NASH, and used mice with conditional overexpression or ablation of Spp1 in myeloid cells and liver MFs, and fed them a high-fat, fructose, and cholesterol diet mimicking the Western diet, to induce NASH.
RESULTS
This study demonstrated that MFs with high expression of SPP1 are enriched in patients and mice with nonalcoholic fatty liver disease (NAFLD), and show metabolic but not pro-inflammatory properties. Conditional knockin of Spp1 in myeloid cells (Spp1) or in hepatic macrophages (Spp1) conferred protection, whereas conditional knockout of Spp1 in myeloid cells (Spp1) worsened NASH. The protective effect was mediated by induction of arginase-2 (ARG2), which enhanced fatty acid oxidation (FAO) in hepatocytes. Induction of ARG2 stemmed from enhanced production of oncostatin-M (OSM) in MFs from Spp1 mice. OSM activated STAT3 signaling, which upregulated ARG2. In addition to hepatic effects, Spp1 also protected through sex-specific extrahepatic mechanisms.
CONCLUSION
MF-derived OPN protects from NASH, by upregulating OSM, which increases ARG2 through STAT3 signaling. Further, the ARG2-mediated increase in FAO reduces steatosis. Therefore, enhancing the OPN-OSM-ARG2 crosstalk between MFs and hepatocytes may be beneficial for patients with NASH.
Topics: Animals; Female; Male; Mice; Diet, High-Fat; Diet, Western; Disease Models, Animal; Liver; Liver Cirrhosis; Macrophages; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Osteopontin
PubMed: 37028770
DOI: 10.1053/j.gastro.2023.03.228 -
Cell Feb 2024Microglia (MG), the brain-resident macrophages, play major roles in health and disease via a diversity of cellular states. While embryonic MG display a large...
Microglia (MG), the brain-resident macrophages, play major roles in health and disease via a diversity of cellular states. While embryonic MG display a large heterogeneity of cellular distribution and transcriptomic states, their functions remain poorly characterized. Here, we uncovered a role for MG in the maintenance of structural integrity at two fetal cortical boundaries. At these boundaries between structures that grow in distinct directions, embryonic MG accumulate, display a state resembling post-natal axon-tract-associated microglia (ATM) and prevent the progression of microcavities into large cavitary lesions, in part via a mechanism involving the ATM-factor Spp1. MG and Spp1 furthermore contribute to the rapid repair of lesions, collectively highlighting protective functions that preserve the fetal brain from physiological morphogenetic stress and injury. Our study thus highlights key major roles for embryonic MG and Spp1 in maintaining structural integrity during morphogenesis, with major implications for our understanding of MG functions and brain development.
Topics: Axons; Brain; Macrophages; Microglia; Morphogenesis
PubMed: 38309258
DOI: 10.1016/j.cell.2024.01.012 -
Frontiers in Immunology 2023Liver metastasis (LM) is a leading cause of cancer-related deaths in CRC patients, whereas the associated mechanisms have not yet been fully elucidated. Therefore, it is...
BACKGROUND
Liver metastasis (LM) is a leading cause of cancer-related deaths in CRC patients, whereas the associated mechanisms have not yet been fully elucidated. Therefore, it is urgently needed to deeply explore novel metastasis accelerators and therapeutic targets of LM-CRC.
METHODS
The bulk RNA sequencing data and clinicopathological information of CRC patients were enrolled from the TCGA and GEO databases. The single-cell RNA sequencing (scRNA-seq) datasets of CRC were collected from and analyzed in the Tumor Immune Single-cell Hub (TISCH) database. The infiltration levels of cancer-associated fibroblasts (CAFs) and macrophages in CRC tissues were estimated by multiple immune deconvolution algorithms. The prognostic values of genes were identified by the Kaplan-Meier curve with a log-rank test. GSEA analysis was carried out to annotate the significantly enriched gene sets. The biological functions of cells were experimentally verified.
RESULTS
In the present study, hundreds of differentially expressed genes (DEGs) were selected in LM-CRC compared to primary CRC, and these DEGs were significantly associated with the regulation of endopeptidase activity, blood coagulation, and metabolic processes. Then, SPP1, CAV1, ANGPTL2, and COLEC11 were identified as the characteristic DEGs of LM-CRC, and higher expression levels of SPP1 and ANGPTL2 were significantly associated with worse clinical outcomes of CRC patients. In addition, ANGPTL2 and SPP1 mainly distributed in the tumor microenvironment (TME) of CRC tissues. Subsequent scRNA-seq analysis demonstrated that ANGPTL2 and SPP1 were markedly enriched in the CAFs and macrophages of CRC tissues, respectively. Moreover, we identified the significantly enriched gene sets in LM-CRC, especially those in the SPP1macrophages and ANGPTL2CAFs, such as the HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION and the HALLMARK_COMPLEMENT. Finally, our experiments proved that ANGPTL2CAFs and SPP1macrophages promote the metastasis of CRC cells.
CONCLUSION
Our study selected four characteristic genes of LM-CRC and identified ANGPTL2CAFs and SPP1macrophages subtypes as metastasis accelerators of CRC which provided a potential therapeutic target for LM-CRC.
Topics: Humans; Algorithms; Angiopoietin-Like Protein 2; Cancer-Associated Fibroblasts; Colorectal Neoplasms; Liver Neoplasms; Macrophages; Osteopontin; Tumor Microenvironment
PubMed: 37691929
DOI: 10.3389/fimmu.2023.1185208 -
Science Advances Jul 2023Macrophages are essential for skeletal muscle homeostasis, but how their dysregulation contributes to the development of fibrosis in muscle disease remains unclear....
Macrophages are essential for skeletal muscle homeostasis, but how their dysregulation contributes to the development of fibrosis in muscle disease remains unclear. Here, we used single-cell transcriptomics to determine the molecular attributes of dystrophic and healthy muscle macrophages. We identified six clusters and unexpectedly found that none corresponded to traditional definitions of M1 or M2 macrophages. Rather, the predominant macrophage signature in dystrophic muscle was characterized by high expression of fibrotic factors, galectin-3 (gal-3) and osteopontin (). Spatial transcriptomics, computational inferences of intercellular communication, and in vitro assays indicated that macrophage-derived Spp1 regulates stromal progenitor differentiation. Gal-3 macrophages were chronically activated in dystrophic muscle, and adoptive transfer assays showed that the gal-3 phenotype was the dominant molecular program induced within the dystrophic milieu. Gal-3 macrophages were also elevated in multiple human myopathies. These studies advance our understanding of macrophages in muscular dystrophy by defining their transcriptional programs and reveal as a major regulator of macrophage and stromal progenitor interactions.
Topics: Mice; Animals; Humans; Transcriptome; Mice, Inbred C57BL; Macrophages; Muscle, Skeletal; Galectin 3; Fibrosis
PubMed: 37418531
DOI: 10.1126/sciadv.add9984 -
Frontiers in Public Health 2023The incidence of primary liver cancer is increasing year by year, with environmental factors playing a non-negligible role. At present, many studies are still disputing...
PURPOSE
The incidence of primary liver cancer is increasing year by year, with environmental factors playing a non-negligible role. At present, many studies are still disputing whether air pollution is associated with primary liver cancer incidence, and it is difficult to draw causal inferences. Therefore, in this study, we used two-sample Mendelian randomization (MR) to assess the causal relationship between air pollution (including PM2.5, PM2.5-10, PM10, nitrogen dioxide and nitrogen oxides) and primary liver cancer risk and its related biomarkers (Alpha-fetoprotein, Osteopontin, Glypican-3 and Arginase-1).
PATIENTS AND METHODS
We used large-scale publicly available genome-wide association studies (GWAS) summary data to conduct MR analyses of European and East Asian populations. Inverse variance weighted (IVW) method was used as the main analysis method, and weighted median model, MR-Egger, simple model and weighted model methods were selected for quality control. Heterogeneity was checked by the Cochran's Q test. The MR-Egger regression and the MR-PRESSO global test detect pleiotropy. The sensitivity analysis was performed using the leave-one-out method.
RESULTS
Between air pollution and primary liver cancer in either European (PM2.5: = 0.993; PM2.5-10: = 0.833; PM10: = 0.257; nitrogen dioxide: = 0.215; nitrogen oxides: = 0.614) or East Asian (PM2.5: = 0.718; PM2.5-10: = 0.362; PM10: = 0.720; nitrogen dioxide: = 0.101; nitrogen oxides: = 0.760) populations were found no statistical association. Notably, there was a causal relationship between nitrogen oxides and Arginase-1, a biomarker associated with hepatocellular differentiation, statistically significant associations remained after deletion for single nucleotide polymorphisms (SNPs) associated with alcohol intake frequency, Body mass index (BMI) and cancers (Beta: 4.46; 95%CI: 0.83-8.08; = 0.015). There was no heterogeneity or pleiotropy in the results.
CONCLUSION
This MR study found no evidence to support a causality between air pollution and primary liver cancer in European and East Asian populations, but nitrogen oxides may affect hepatocellular differentiation.
Topics: Humans; Air Pollution; Arginase; East Asian People; Genome-Wide Association Study; Liver Neoplasms; Mendelian Randomization Analysis; Nitrogen Dioxide; Nitrogen Oxides; Particulate Matter; European People; Asia, Eastern; Europe
PubMed: 37575092
DOI: 10.3389/fpubh.2023.1212301 -
Circulation Research Sep 2023Using proteomics, we aimed to reveal molecular types of human atherosclerotic lesions and study their associations with histology, imaging, and cardiovascular outcomes.
BACKGROUND
Using proteomics, we aimed to reveal molecular types of human atherosclerotic lesions and study their associations with histology, imaging, and cardiovascular outcomes.
METHODS
Two hundred nineteen carotid endarterectomy samples were procured from 120 patients. A sequential protein extraction protocol was employed in conjunction with multiplexed, discovery proteomics. To focus on extracellular proteins, parallel reaction monitoring was employed for targeted proteomics. Proteomic signatures were integrated with bulk, single-cell, and spatial RNA-sequencing data, and validated in 200 patients from the Athero-Express Biobank study.
RESULTS
This extensive proteomics analysis identified plaque inflammation and calcification signatures, which were inversely correlated and validated using targeted proteomics. The inflammation signature was characterized by the presence of neutrophil-derived proteins, such as S100A8/9 (calprotectin) and myeloperoxidase, whereas the calcification signature included fetuin-A, osteopontin, and gamma-carboxylated proteins. The proteomics data also revealed sex differences in atherosclerosis, with large-aggregating proteoglycans versican and aggrecan being more abundant in females and exhibiting an inverse correlation with estradiol levels. The integration of RNA-sequencing data attributed the inflammation signature predominantly to neutrophils and macrophages, and the calcification and sex signatures to smooth muscle cells, except for certain plasma proteins that were not expressed but retained in plaques, such as fetuin-A. Dimensionality reduction and machine learning techniques were applied to identify 4 distinct plaque phenotypes based on proteomics data. A protein signature of 4 key proteins (calponin, protein C, serpin H1, and versican) predicted future cardiovascular mortality with an area under the curve of 75% and 67.5% in the discovery and validation cohort, respectively, surpassing the prognostic performance of imaging and histology.
CONCLUSIONS
Plaque proteomics redefined clinically relevant patient groups with distinct outcomes, identifying subgroups of male and female patients with elevated risk of future cardiovascular events.
Topics: Female; Humans; Male; Proteomics; Sex Characteristics; Versicans; alpha-2-HS-Glycoprotein; Atherosclerosis; Calcinosis
PubMed: 37646165
DOI: 10.1161/CIRCRESAHA.123.322590 -
Nature Communications Nov 2023The initiation and progression of cancer are intricately linked to the tumor microenvironment (TME). Understanding the function of specific cancer-TME interactions poses...
The initiation and progression of cancer are intricately linked to the tumor microenvironment (TME). Understanding the function of specific cancer-TME interactions poses a major challenge due in part to the complexity of the in vivo microenvironment. Here we predict cancer-TME interactions from single cell transcriptomic maps of both human colorectal cancers (CRCs) and mouse CRC models, ask how these interactions are altered in human tumor organoid (tumoroid) cultures, and functionally recapitulate human myeloid-carcinoma interactions in vitro. Tumoroid cultures suppress gene expression programs involved in inflammation and immune cell migration, providing a reductive platform for re-establishing carcinoma-immune cell interactions in vitro. Introduction of human monocyte-derived macrophages into tumoroid cultures instructs macrophages to acquire immunosuppressive and pro-tumorigenic gene expression programs similar to those observed in vivo. This includes hallmark induction of SPP1, encoding Osteopontin, an extracellular CD44 ligand with established oncogenic effects. Taken together, these findings offer a framework for understanding CRC-TME interactions and provide a reductionist tool for modeling specific aspects of these interactions.
Topics: Animals; Mice; Humans; Tumor Microenvironment; Macrophages; Carcinogenesis; Colorectal Neoplasms; Carcinoma
PubMed: 38036590
DOI: 10.1038/s41467-023-43746-6