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 (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-deficien

SUBMITTER: Weigel C 

PROVIDER: S-EPMC9931683 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature