Crosstalk of sphingolipids and inflammasomes modulates tumor microenvironment and promotes cancer progression

Abstract

Sphingosine-1-phosphate (S1P), a bioactive lipid, plays important roles in tumor development through its ability to promote tumor cell growth, migration, and invasion. S1P, synthesized by sphingosine kinase 1 and 2 (SK1 and SK2), can initiate multiple signal events through intracellular and extracellular mechanisms. In human cancer patients, increased levels of S1P and SK1 are correlated with poor prognosis and high incidence of diseases recurrence. How sphingolipid signaling regulates the function of immune cells and inflammation during tumor development remains poorly understood. Our results demonstrate that sphingolipid-induced inflammasome activation and IL-1β production promotes tumorigenesis and metastasis. Interestingly, our data indicate that SK-1/S1P signaling induces inflammasome activation and IL-1 production. We found that in MMTV-PyT transgenic mouse mammary gland tumor model, genetic loss of SphK1 significantly inhibited breast cancer progression and metastasis, accompanied by reduced levels of IL-1β at primary tumors and metastatic sites. Our results further show that SK1 and S1P modulate tumor microenvironments through induction of inflammasome activation and recruitment of myeloid cells. These findings indicate that the cross-talk between the SK1/S1P and inflammasome/IL-1 pathways promotes tumor growth and metastasis.