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

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

PROVIDER: PRJNA562928 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10044345.fastq.gz	Fastqsanger.gz
	SRR10044346.fastq.gz	Fastqsanger.gz
	SRR10044347.fastq.gz	Fastqsanger.gz
	SRR10044348.fastq.gz	Fastqsanger.gz
	SRR10044349.fastq.gz	Fastqsanger.gz

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

Project description: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.

2020-01-01 | GSE136655 | GEO

Sphingosine Kinase 2 in Stromal Fibroblasts Creates a Hospitable Tumor Microenvironment in Breast Cancer.

Project description:Reciprocal interactions between breast cancer cells and the tumor microenvironment (TME) 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 (CAF) by upregulating stromal p53, which restrained production of tumor-promoting factors to reprogram the TME and to 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 TME and to enhance therapeutic efficacy.SignificanceSphingosine kinase 2 (SphK2) facilitates the activation of stromal fibroblasts to tumor-promoting cancer-associated fibroblasts by suppressing host p53 activity, revealing SphK2 as a potential target to reprogram the TME.

| S-EPMC9931683 | biostudies-literature

Impact of Sphingosine Kinase-1 knock out in neonatal mice lungs

Project description:Sphingosine Kinase-1 knock out protects against hyperoxic lung injury One day old Wild type (WT) control and Sphingosine Kinase-1 knock out (SphK-1 KO)pups exposed to room air (RA) or hyperoxia (HO). Microarray based profiling of lung tissue after 7 days of hyperoxia of 75%

2016-10-30 | GSE87350 | GEO

Sphingosine kinase 1 regulates the pulmonary vascular immune response

Project description:Sphingosine kinase 1 regulates the pulmonary vascular immune response

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Sphingosine kinase 1 regulates the pulmonary vascular immune response

Project description:Aberrant proliferation of pulmonary arterial smooth muscle (PASMCs) cells are a defining characteristic of pulmonary arterial hypertension (PAH) and leads to increased vascular resistance, elevated pulmonary pressure, and right heart failure. The Sphingosine kinase 1 (SPHK1)/Sphingosine-1 phosphate/ Sphingosine-1 phosphate receptor 2 pathway promotes vascular remodeling and induces PAH. The aim of this study was to identify genes and cellular processes that are modulated by over-expression of SPHK1 in human PASMCs (hPASMCs). RNA was purified and submitted for RNA sequencing to identify differentially expressed genes. Using a corrected p-value threshold of <0.05, there were 294 genes significantly up-regulated while 179 were significantly down-regulated. Predicted effects of these differentially expressed genes was evaluated using the freeware tool Enrichr to assess general gene set over-representation (enrichment) and Ingenuity Pathway Analysis (IPA™) for upstream regulator predictions. We found a strong change in genes that regulated the cellular immune response. IL6, STAT1, and PARP9, were elevated in response to SPHK1 over-expression in hPASMCs. The gene set enrichment mapped to a few immune modulatory signaling networks, including IFNG. Furthermore, STAT1 protein was elevated in primary hPASMCs isolated from PAH patients. In conclusion, these data suggest a role of Sphk1 regulates pulmonary vascular immune response in PAH.

2021-06-22 | GSE174304 | GEO

Dual-species microarray for assessing gene expression in stromal microenvironment, cancer cells and their interactions

Project description:This SuperSeries is composed of the following subset Series: GSE23054: Dual-species microarray for assessing gene expression in stromal microenvironment, cancer cells and their interactions (v1 array) GSE23364: Dual-species microarray for assessing gene expression in stromal microenvironment, cancer cells and their interactions (v2 array) Refer to individual Series

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Proteomics of murine melanoma tumor cells upon sphingosine kinase-1 inhibition

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2019-12-17 | PXD016535 | Pride

Targeting sphingosine kinase by ABC294640 induces KSHV-infected endothelial cell autophagic death

Project description:KSHV is a principal causative agent of Kaposi's Sarcoma (KS). Despite this knowledge about the close relationship between sphingolipid metablism and solid tumors development, the role of sphingolipid metablism in KSHV-related malignancies remains mostly unclear. We report that targeting sphingosine kinase 2 (SphK2) by a selective inhibitor, ABC294640, significantly induces KSHV+ TIVE-LTC autophagic death. By using microarray analysis, we have identified the global gene profile affected by ABC294640 within KSHV+ TIVE-LTC and several novel “druggable” candidates closely related to cancer cell survival/growth. Finally, we found that targeting TIVE-LTC by ABC294640 effectively suppressed KSHV tumorigenicity by using a KS-like nude mice model.

2016-11-01 | GSE74338 | GEO

Human Subperitoneal Fibroblasts and Cancer Cell Interaction Creates Microenvironment Enhancing Tumor Progression and Metastasis

Project description:Fibroblasts isolated from human colon submucosal and subperitoneal layer were stimulated by colon cancer cell line (DLD-1) cultured medium. Peritoneal invasion in colon cancer is an important prognostic factor, and the fibrosis with α-SMA was a significant pathological feature of the cancer microenvironment formed by peritoneal invasion (CMPI). The result indicated that the gene expression of subperitoneal fibroblasts showed more various gene modification than submucosal fibroblasts. And ACTA2 expression was higher in fibroblasts from subperitoneal layer than that from submucosal layer. Together with this concordant stromal protein expression in CMPI, this in vitro model is able to reflect the special microenvironment in CMPI. 3 cases of human colon submucosal and subperitoneal fibroblasts were isolated, and these fibroblasts were stimulated with DLD-1 cultured medium. Total RNA were extracted from these samples and hybridized in Affymetrix microarray to compare their gene expression changes through the DLD-1 stimulation

2014-02-20 | E-GEOD-53059 | biostudies-arrayexpress

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

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2021-10-14 | GSE173886 | GEO

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