GSE169443
Pro-survival lipid metabolism activates intracellular complement signaling to induce inflammasome-mediated tumor metastasis
Tumor metastasis remains one of the major causes of cancer-related deaths in patients with solid tumors. Mechanisms by which metabolic alterations regarding pro-survival lipid signaling   activation in inducing cancer cell migration and metastasis are largely unknown. Here, we demonstrate that S1P metabolism activates endogenous complement signaling for inducing tumor metastasis via inducing inflammasome-mediated pro-inflammation. Our studies using molecular, pharmacologic and genetic tools showed that activation of sphingosine 1-phosphate (S1P) and S1P receptor 1 (S1P/S1PR1) induces tumor metastasis via enhanced intracellular complement signaling by the regulation of the C3-PPIL1 complex and subsequent inflammasome activation in cancer cells and in vivo xenograft-derived tumors. Overall design: PPIL1 gene was stably knocked out in B16 cell line using CRISPR-Cas9, and treated with JTE-013+ S1P lyase inhibitor (DPO). Total RNA was extracted from the PPIL1 KO treated vs untreated samples,  as well as  scrambled treated vs untreated as controls.