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Sphingosine kinase 2 in stromal fibroblasts creates a hospitable tumor microenvironment in breast cancer

ABSTRACT: Reciprocal interactions between breast cancer cells and the tumor microenvironment are important for cancer progression and metastasis. We report here that the deletion or inhibition of sphingosine kinase 2 (SphK2), which produces sphingosine-1-phosphate (S1P), markedly suppresses syngeneic breast tumor growth and lung metastasis in mice by creating a hostile microenvironment for tumor growth and invasion. SphK2 deficiency decreased S1P and concomitantly increased ceramides, including C16-ceramide, in stromal fibroblasts. Ceramide accumulation suppressed activation of cancer-associated fibroblasts (CAFs) by upregulating stromal p53, which restrained production of tumor-promoting factors to reprogram the tumor microenvironment and restrict breast cancer establishment. Ablation of p53 in SphK2-deficient fibroblasts reversed these effects, enabled CAF activation and promoted tumor growth and invasion. These data uncovered a novel role of SphK2 in regulating non-cell autonomous functions of p53 in stromal fibroblasts and their transition to tumor-promoting CAFs, paving the way for the development of a strategy to target the tumor microenvironment and enhance therapeutic efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE136655 | GEO | 2020/01/01

REPOSITORIES: GEO

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Next Generation Sequencing Facilitates Quantitative Analysis of Wild Type, SphK1-/- and SphK2-/- fibroblasts Transcriptomes

Project description:In numerous forms of organ injury, interstitial fibrosis is a final common pathway. Despite recent epidemiological studies, therapies to focus on fibrosis and to delay progressive renal failure are limited. Previously our group showed that sphingosine kinase 2 deficient-mice (SphK2-/-) develop less fibrosis in folic acid-induced or unilateral ischemia-reperfusion injury (IRI)-induced kidney fibrosis models. Sphingosine 1-phosphate (S1P) is produced by two sphingosine kinase isoforms (SphK1 and SphK2). S1P is involved in diverse functions, but the role of S1P produced by SphK2 is gathering attention as treatments focused on epigenetics have been developed. SphK2 is primarily located in the nucleus and S1P produced by SphK2 inhibits histone deacetylase (HDAC) and changes in histone acetylation status, which can lead to an altered target gene expression. We identified that bone marrow stromal cell antigen-1 (Bst1/CD157) is a gene related with kidney fibrosis based on the combination of genome-wide analysis and in vivo screening. SphK2 regulates Bst1 expression and Bst1-/- mice develop less fibrosis after unilateral IRI and are protected against renal bilateral IRI. Bone marrow chimera experiments further revealed the importance of Bst1 expression on hematopoietic cells. Furthermore we identified the role of Bst1 expression in neutrophils for inducing renal ischemia-reperfusion injury and fibrosis.

2019-09-01 | GSE103062 | GEO

Genome-wide maps of histone acetylation status in renal fibroblasts.

2019-09-01 | GSE103058 | GEO

Expression data from C42B prostate cancer cell line treated with enzalutamide and/or sphingosine kinase inhibitor PF-543 or ABC294640

Project description:Epidemiological and molecular evidence indicate that sphingolipids may play a role in the resistance of prostate cancer to androgen receptor signalling inhibitors such as enzalutamide, through the metabolism of ceramide into sphingosine-1-phosphate (S1P) which activates specific G-protein coupled receptors present on cancer cells and immune cells. Sphingosine kinase inhibitors which prevent the production of S1P have anti-cancer effects in vitro and in animal models. Our work showed that SPHK inhibitors can enhance the efficacy of enzalutamide in prostate cancer cell lines. We used microarrays to investigate the transcriptomic changes from the combination of enzalutamide with the SPHK1 inhibitor PF543, or SPHK2 inhibitor ABC294640, in C42B, one of the prostate cancer cell line.

2021-10-14 | GSE173886 | GEO

RNA seq of human fibroblasts treated with Rocuronium bromide

Project description:Cancer associated fibroblasts (CAFs) as the main stromal cells in tumor microenvironment can provide metabolic links with tumor cells through metabolic derivatives such as cytokines released, creating a favorable metabolic microenvironment for tumor progression. Recent in vitro and in vivo studies have discovered that anesthetics can affect tumor malignancy. However, the mechanism is unknown, and the total-body dosage and short-term treatment duration of anesthetic drugs are still far from tumor treatment. Now, our study focuses on the effect of rocuronium bromide (RB) on CAFs. In order to restore the true effects of CAFs by RB, we studied the global transcriptomic signatures of human fibroblasts derived from different tissues (skin HS-27; lung TIG-1; dermal CRL-7815) by 160 μg/mL RB to find the target genes responding to RB.

2022-05-22 | E-MTAB-11728 | biostudies-arrayexpress

S1P lyase deficiency disrupts lipid homeostasis in liver

Project description:The cleavage of sphingoid base phosphates by sphingosine-1-phosphate (S1P) lyase to produce phosphoethanolamine and a fatty aldehyde is the final degradative step in the sphingolipid metabolic pathway. We have studied mice with an inactive S1P lyase gene and have found that, in addition to the expected increase of sphingoid base phosphates, other sphingolipids (including sphingosine, ceramide, and sphingomyelin) were substantially elevated in the serum and /or liver of these mice. This latter increase is consistent with a reutilization of the sphingosine backbone for sphingolipid synthesis due to its inability to exit the sphingolipid metabolic pathway. Furthermore, the S1P lyase deficiency resulted in changes in the levels of serum and liver lipids not directly within the sphingolipid pathway, including phospholipids, triacyglycerol, diacylglycerol, and cholesterol. Even though lipids in serum and lipid storage were elevated in liver, adiposity was reduced in the S1P lyase-deficient mice. Microarray analysis of lipid metabolism genes in liver showed that the S1P lyase deficiency caused widespread changes in their expression pattern. These results demonstrate that S1P lyase is a key regulator of the levels of multiple sphingolipid substrates and reveal functional links between the sphingolipid metabolic pathway and other lipid metabolic pathways that may be mediated by shared lipid substrates and changes in gene expression programs. The disturbance of lipid homeostasis by altered sphingolipid levels may be relevant to metabolic diseases. Experiment Overall Design: RNA samples from liver for three sphingosine-1-phosphate lyase knock-out and three WT mice.

2010-02-05 | E-GEOD-18745 | biostudies-arrayexpress

Pseudomonas-derived Ceramidase Induces Production of Inflammatory Mediators from Human Keratinocytes via Sphingosine-1-Phosphate

Project description:A Pseudomonas aeruginosa-derived neutral ceramidase (PaCDase) isolated from a patient with atopic dermatitis was shown to effectively degrade ceramide in the presence of Staphylococcus aureus-derived lipids or neutral detergents. To understand the effect of ceramide metabolites on the functions of differentiating keratinocytes, we have conducted genes expressions analysis from PaCDase-, sphingosine-1-phosphate (S1P)-treated or untreated three-dimensionally cultured human primary keratinocytes, which form a stratum corneum, in the presence of Triton X-100 using high resolution DNA microarray. To evaluate the effects of PaCDase and S1P on keratinocyte functions, we applied an epicutaneous 24-h patch test on the EPI-Model in keratinocyte serum-free medium (keratinocyte-SFM) (Invitrogen; Carlsbad, CA, USA) by the method of Spiekstra et al. [25] with some modification. The Triton X-100 treated samples were labeled using Cy5, and the PaCDase or S1P samples were labeled with Cy3.

2014-12-25 | E-GEOD-53670 | biostudies-arrayexpress

Aging stress and ceramide dependent RNA sequencing expression profiling depends on ceramide synthase 6

Project description:The bioactive sphingolipid ceramide, generated by ceramide synthase, is an adaptive stress effector induced in response to various stress stimuli such as aging. In fact, ceramide synthase (CerS) was first discovered in yeast as a longevity assurance gene (LAG1), as the reduced ceramide generation consequent to LAG1 deletion increased longevity. There are six homologues of mammalian LAG1/ceramide synthases (CerS1-6) that generate ceramides with different fatty acid chain lengths with distinct functions and hydrophobicity. Ceramide can be metabolized by sphingosine kinase 1 or 2 for the generation of pro-survival sphingosine 1-phosphate (S1P), which enhances immune cell egress to the blood stream, activating immune function. Ceramide is known to induce mitophagy and cell death. Here we investigated the role of this sphingolipid pathway in immune function, specifically T cell functions, via high throughput expression profiling.

2021-01-01 | GSE148498 | GEO

Proteome comparison of a new human cholangiocarcinoma 3D co-culture tumor model to 3D single cultures.

Project description:Cholangiocarcinomas (CCA) are characterized by their desmoplastic and hypervascularized tumor microenvironment (TME) which is mainly composed of tumor cells and cancer-associated fibroblasts (CAFs). CAFs play a pivotal role in tumor progression, angiogenesis, metastasis and the development of therapy resistance. To our knowledge, no continuous human in vivo-like co-culture model is available for research. Therefore, we aimed to establish a new model that mimics the desmoplastic environment typically seen in CCA. Proteomic data comparing the new CCA tumor cell line with our co-culture tumor model (CCTM) indicated a higher correlation of the CCTM with physiological CCA characteristics according to literature. A pro-angiogenic TME that is typically observed in CCA could also be simulated in the CCTM group. Further analysis of secreted proteins revealed CAFs to be the main source for these angiogenic factors. Our CCTM represents a new, reproducible and easy-to-handle 3D CCA model for preclinical studies focusing on CCA-stromal crosstalk, tumor angiogenesis and invasion, the immunosuppressive microenvironment and the involvement of CAFs in the way that drug resistance develops.

2023-05-10 | PXD037649 | Pride

Identification of stromally expressed molecules in the prostate by Tag profiling of cancer-associated fibroblasts, normal fibroblasts and fetal prostate

Project description:The stromal microenvironment plays key roles in prostate development and cancer. Cancer associated fibroblasts (CAFs) and other stromal cells stimulate tumourigenesis via several mechanisms including the expression of pro-tumourigenic factors. Mesenchyme (embryonic stroma) controls prostate organogenesis, and in some circumstances can re-differentiate prostate tumours. Epithelia are regulated by powerful paracrine signalling from the stroma in both development and disease, and identification of these stromal signals is important. We have applied next-generation Tag profiling to fetal human prostate, normal human prostate fibroblasts (NPFs) and CAFs to identify molecules expressed in prostatic stroma Each sample was used for Tag library construction, by Solexa Inc

2011-10-22 | E-GEOD-25018 | biostudies-arrayexpress

Pseudomonas-derived Ceramidase Induces Production of Inflammatory Mediators from Human Keratinocytes via Sphingosine-1-Phosphate

2014-12-25 | GSE53670 | GEO

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