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Cancer Cell Jun 2021The mesenchymal subtype of glioblastoma is thought to be determined by both cancer cell-intrinsic alterations and extrinsic cellular interactions, but remains poorly...
The mesenchymal subtype of glioblastoma is thought to be determined by both cancer cell-intrinsic alterations and extrinsic cellular interactions, but remains poorly understood. Here, we dissect glioblastoma-to-microenvironment interactions by single-cell RNA sequencing analysis of human tumors and model systems, combined with functional experiments. We demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo, by macrophage-derived oncostatin M (OSM) that interacts with its receptors (OSMR or LIFR) in complex with GP130 on glioblastoma cells and activates STAT3. We show that MES-like glioblastoma states are also associated with increased expression of a mesenchymal program in macrophages and with increased cytotoxicity of T cells, highlighting extensive alterations of the immune microenvironment with potential therapeutic implications.
Topics: Animals; Brain Neoplasms; Cells, Cultured; Cytokine Receptor gp130; Cytotoxicity, Immunologic; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Leukemia Inhibitory Factor Receptor alpha Subunit; Mice, Inbred C57BL; Mice, Transgenic; Oncostatin M; Oncostatin M Receptor beta Subunit; STAT3 Transcription Factor; T-Lymphocytes; Tumor Microenvironment; Tumor-Associated Macrophages; Mice
PubMed: 34087162
DOI: 10.1016/j.ccell.2021.05.002 -
Nature Medicine May 2017Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract...
Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are mainstay therapies for IBD. However, up to 40% of patients are nonresponsive to anti-TNF agents, which makes the identification of alternative therapeutic targets a priority. Here we show that, relative to healthy controls, inflamed intestinal tissues from patients with IBD express high amounts of the cytokine oncostatin M (OSM) and its receptor (OSMR), which correlate closely with histopathological disease severity. The OSMR is expressed in nonhematopoietic, nonepithelial intestinal stromal cells, which respond to OSM by producing various proinflammatory molecules, including interleukin (IL)-6, the leukocyte adhesion factor ICAM1, and chemokines that attract neutrophils, monocytes, and T cells. In an animal model of anti-TNF-resistant intestinal inflammation, genetic deletion or pharmacological blockade of OSM significantly attenuates colitis. Furthermore, according to an analysis of more than 200 patients with IBD, including two cohorts from phase 3 clinical trials of infliximab and golimumab, high pretreatment expression of OSM is strongly associated with failure of anti-TNF therapy. OSM is thus a potential biomarker and therapeutic target for IBD, and has particular relevance for anti-TNF-resistant patients.
Topics: Adult; Aged; Animals; Antibodies, Monoclonal; Case-Control Studies; Chemokines; Colitis; Disease Models, Animal; Female; Flow Cytometry; Gastrointestinal Agents; Gene Expression Profiling; Humans; Immunoblotting; Immunohistochemistry; Inflammation; Inflammatory Bowel Diseases; Infliximab; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Mice; Mice, Knockout; Middle Aged; Oncostatin M; Oncostatin M Receptor beta Subunit; Real-Time Polymerase Chain Reaction; Tumor Necrosis Factor-alpha; Young Adult
PubMed: 28368383
DOI: 10.1038/nm.4307 -
The Journal of Clinical Investigation Apr 2022The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the...
The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the reprogramming of the TME is not well understood. Here, we provide evidence of the role of the cytokine oncostatin M (OSM) as central node for multicellular interactions between immune and nonimmune stromal cells and the epithelial cancer cell compartment. OSM receptor (OSMR) deletion in a multistage breast cancer model halted tumor progression. We ascribed causality to the stromal function of the OSM axis by demonstrating reduced tumor burden of syngeneic tumors implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumors revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype and elicited the secretion of VEGF and proinflammatory chemokines CXCL1 and CXCL16, leading to increased myeloid cell recruitment. Collectively, our data support the notion that the stromal OSM/OSMR axis reprograms the immune and nonimmune microenvironment and plays a key role in breast cancer progression.
Topics: Animals; Breast Neoplasms; Female; Fibroblasts; Humans; Mice; Oncostatin M; Signal Transduction; Tumor Microenvironment
PubMed: 35192545
DOI: 10.1172/JCI148667 -
Nature Communications Dec 2021Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a complex microenvironment. Dichotomous tumour-promoting and -restrictive roles have been ascribed to...
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a complex microenvironment. Dichotomous tumour-promoting and -restrictive roles have been ascribed to the tumour microenvironment, however the effects of individual stromal subsets remain incompletely characterised. Here, we describe how heterocellular Oncostatin M (OSM) - Oncostatin M Receptor (OSMR) signalling reprograms fibroblasts, regulates tumour growth and metastasis. Macrophage-secreted OSM stimulates inflammatory gene expression in cancer-associated fibroblasts (CAFs), which in turn induce a pro-tumourigenic environment and engage tumour cell survival and migratory signalling pathways. Tumour cells implanted in Osm-deficient (Osm) mice display an epithelial-dominated morphology, reduced tumour growth and do not metastasise. Moreover, the tumour microenvironment of Osm animals exhibit increased abundance of α smooth muscle actin positive myofibroblasts and a shift in myeloid and T cell phenotypes, consistent with a more immunogenic environment. Taken together, these data demonstrate how OSM-OSMR signalling coordinates heterocellular interactions to drive a pro-tumourigenic environment in PDA.
Topics: Adenocarcinoma; Animals; Cancer-Associated Fibroblasts; Carcinoma, Pancreatic Ductal; Cell Communication; Cell Line, Tumor; Cell Proliferation; Granulocyte-Macrophage Colony-Stimulating Factor; Immunosuppression Therapy; Inflammation; Macrophages; Male; Mice, Inbred C57BL; Neoplasm Metastasis; Oncostatin M; Pancreatic Neoplasms; Pancreatic Stellate Cells; Receptors, Oncostatin M; Signal Transduction; Tumor Microenvironment; Mice
PubMed: 34921158
DOI: 10.1038/s41467-021-27607-8 -
Journal For Immunotherapy of Cancer Mar 2021Tumor-associated neutrophils (TANs) and macrophages (TAMs) can each influence cancer growth and metastasis, but their combined effects in intrahepatic cholangiocarcinoma...
BACKGROUND
Tumor-associated neutrophils (TANs) and macrophages (TAMs) can each influence cancer growth and metastasis, but their combined effects in intrahepatic cholangiocarcinoma (ICC) remain unclear.
METHODS
We explored the distributions of TANs and TAMs in patient-derived ICC samples by multiplex immunofluorescent staining and tested their separate and combined effects on ICC in vitro and in vivo. We then investigated the mechanistic basis of the effects using PCR array, western blot analysis and ELISA experiments. Finally, we validated our results in a tissue microarray composed of primary tumor tissues from 359 patients with ICC.
RESULTS
The spatial distributions of TANs and TAMs were correlated with each other in patient-derived ICC samples. Interaction between TANs and TAMs enhanced the proliferation and invasion abilities of ICC cells in vitro and tumor progression in a mouse xenograft model of ICC. TANs and TAMs produced higher levels of oncostatin M and interleukin-11, respectively, in co-culture than in monoculture. Both of those cytokines activated STAT3 signaling in ICC cells. Knockdown of STAT3 abolished the protumor effect of TANs and TAMs on ICC. In tumor samples from patients with ICC, increased TAN and TAM levels were correlated with elevated p-STAT3 expression. All three of those factors were independent predictors of patient outcomes.
CONCLUSIONS
TANs and TAMs interact to promote ICC progression by activating STAT3.
Topics: Animals; Bile Duct Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cholangiocarcinoma; Coculture Techniques; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Interleukin-11; Male; Mice, Inbred NOD; Mice, SCID; Neoplasm Invasiveness; Neutrophils; Oncostatin M; Phosphorylation; STAT3 Transcription Factor; Signal Transduction; Tumor Microenvironment; Tumor-Associated Macrophages; Mice
PubMed: 33692217
DOI: 10.1136/jitc-2020-001946 -
Cell Stem Cell Apr 2019Hair growth can be induced from resting mouse hair follicles by topical application of JAK inhibitors, suggesting that JAK-STAT signaling is required for maintaining...
Hair growth can be induced from resting mouse hair follicles by topical application of JAK inhibitors, suggesting that JAK-STAT signaling is required for maintaining hair follicle stem cells (HFSCs) in a quiescent state. Here, we show that Oncostatin M (OSM), an IL-6 family cytokine, negatively regulates hair growth by signaling through JAK-STAT5 to maintain HFSC quiescence. Genetic deletion of the OSM receptor or STAT5 can induce premature HFSC activation, suggesting that the resting telogen stage is actively maintained by the hair follicle niche. Single-cell RNA sequencing revealed that the OSM source is not intrinsic to the hair follicle itself and is instead a subset of TREM2 macrophages that is enriched within the resting follicle and deceases immediately prior to HFSC activation. In vivo inhibition of macrophage function was sufficient to induce HFSC proliferation and hair cycle induction. Together these results clarify how JAK-STAT signaling actively inhibits hair growth.
Topics: Animals; Cell Cycle; Cell Proliferation; Dermis; Female; Hair; Hair Follicle; Humans; Janus Kinase 2; Macrophages; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oncostatin M; Receptors, Immunologic; STAT5 Transcription Factor; Signal Transduction; Stem Cells
PubMed: 30930146
DOI: 10.1016/j.stem.2019.01.011 -
The Journal of Experimental Medicine Aug 2021The wound healing process that occurs after spinal cord injury is critical for maintaining tissue homeostasis and limiting tissue damage, but eventually results in a...
The wound healing process that occurs after spinal cord injury is critical for maintaining tissue homeostasis and limiting tissue damage, but eventually results in a scar-like environment that is not conducive to regeneration and repair. A better understanding of this dichotomy is critical to developing effective therapeutics that target the appropriate pathobiology, but a major challenge has been the large cellular heterogeneity that results in immensely complex cellular interactions. In this study, we used single-cell RNA sequencing to assess virtually all cell types that comprise the mouse spinal cord injury site. In addition to discovering novel subpopulations, we used expression values of receptor-ligand pairs to identify signaling pathways that are predicted to regulate specific cellular interactions during angiogenesis, gliosis, and fibrosis. Our dataset is a valuable resource that provides novel mechanistic insight into the pathobiology of not only spinal cord injury but also other traumatic disorders of the CNS.
Topics: Angiopoietins; Animals; Astrocytes; Cell Communication; Chemotaxis; Female; Fibroblasts; Fibrosis; Gliosis; Inflammation; Interleukin-6; Ligands; Macrophages; Mice, Inbred C57BL; Myeloid Cells; Neuroglia; Oncostatin M; Receptors, Oncostatin M; Signal Transduction; Single-Cell Analysis; Spinal Cord Injuries; Time Factors; Transcriptome; Vascular Endothelial Growth Factor A; Mice
PubMed: 34132743
DOI: 10.1084/jem.20210040 -
Science Advances Apr 2023CD34 cells improve the perfusion and function of ischemic limbs in humans and mice. However, there is no direct evidence of the differentiation potential and functional...
CD34 cells improve the perfusion and function of ischemic limbs in humans and mice. However, there is no direct evidence of the differentiation potential and functional role of these cells in the ischemic muscle microenvironment. Here, we combined the single-cell RNA sequencing and genetic lineage tracing technology, then provided exact single-cell atlases of normal and ischemic limb tissues in human and mouse, and consequently found that bone marrow (BM)-derived macrophages with antigen-presenting function migrated to the ischemic site, while resident macrophages underwent apoptosis. The macrophage oncostatin M (OSM) regulatory pathway was specifically turned on by ischemia. Simultaneously, BM CD34-derived proregenerative fibroblasts were recruited to the ischemia niche, where they received macrophage-released OSM and promoted angiopoietin-like protein-associated angiogenesis. These findings provided mechanisms on the cellular events and cell-cell communications during tissue ischemia and regeneration and provided evidence that CD34 cells serve as fibroblast progenitors promoting tissue regeneration.
Topics: Humans; Mice; Animals; Oncostatin M; Signal Transduction; Ischemia; Macrophages; Fibroblasts
PubMed: 37043578
DOI: 10.1126/sciadv.add2632 -
Science Translational Medicine Nov 2021Chronic itch is a major symptom of many inflammatory skin diseases. This type of pruritus is thought to be facilitated by cytokines that activate cutaneous nerve fibers;...
Chronic itch is a major symptom of many inflammatory skin diseases. This type of pruritus is thought to be facilitated by cytokines that activate cutaneous nerve fibers; however, the molecular components and mechanisms involved are poorly understood. We found that the cytokine oncostatin M (OSM) is highly up-regulated in psoriasis, atopic dermatitis, and cutaneous T cell lymphoma, diseases associated with chronic itch. OSM receptor (OSMR) is expressed by itch-selective natriuretic polypeptide B (Nppb) neurons, and single-cell sequencing showed that OSM is mainly produced by dermal T cells and monocytes. Unlike canonical pruritogens, OSM does not activate sensory neurons. Instead, it sensitizes neurons by potentiating neural responses to pruritogens and by enhancing neural excitability. Knockout of OSMR in sensory neurons attenuated OSM-sensitized itch and inflammatory itch in mice, and pharmacological antagonism of the OSMR complex effectively alleviated pruritus in experimental inflammatory dermatitis in a rodent model. Together, our results uncover OSM as an itch neuromodulator and reveal OSM signal transduction as a potential target for antipruritic therapy.
Topics: Animals; Gene Knockout Techniques; Mice; Mice, Knockout; Oncostatin M; Oncostatin M Receptor beta Subunit; Pruritus; Sensory Receptor Cells; Signal Transduction; Skin
PubMed: 34757808
DOI: 10.1126/scitranslmed.abe3037 -
Molecular Cancer Research : MCR Sep 2023Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) frequently present with advanced metastatic disease and exhibit a poor response to therapy, resulting in...
UNLABELLED
Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) frequently present with advanced metastatic disease and exhibit a poor response to therapy, resulting in poor outcomes. The tumor microenvironment cytokine Oncostatin-M (OSM) initiates PDAC plasticity, inducing the reprogramming to a stem-like/mesenchymal state, which enhances metastasis and therapy resistance. Using a panel of PDAC cells driven through epithelial-mesenchymal transition (EMT) by OSM or the transcription factors ZEB1 or SNAI1, we find that OSM uniquely induces tumor initiation and gemcitabine resistance independently of its ability to induce a CD44HI/mesenchymal phenotype. In contrast, while ZEB1 and SNAI1 induce a CD44HI/mesenchymal phenotype and migration comparable with OSM, they are unable to promote tumor initiation or robust gemcitabine resistance. Transcriptomic analysis identified that OSM-mediated stemness requires MAPK activation and sustained, feed-forward transcription of OSMR. MEK and ERK inhibitors prevented OSM-driven transcription of select target genes and stem-like/mesenchymal reprogramming, resulting in reduced tumor growth and resensitization to gemcitabine. We propose that the unique properties of OSMR, which hyperactivates MAPK signaling when compared with other IL6 family receptors, make it an attractive therapeutic target, and that disrupting the OSM-OSMR-MAPK feed-forward loop may be a novel way to therapeutically target the stem-like behaviors common to aggressive PDAC.
IMPLICATIONS
Small-molecule MAPK inhibitors may effectively target the OSM/OSMR-axis that leads to EMT and tumor initiating properties that promote aggressive PDAC.
Topics: Humans; Receptors, Oncostatin M; Signal Transduction; Oncostatin M; Pancreatic Neoplasms; Epithelial-Mesenchymal Transition; Carcinoma, Pancreatic Ductal; Tumor Microenvironment
PubMed: 37310811
DOI: 10.1158/1541-7786.MCR-22-0715