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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

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

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

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

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