biostudies-literatureJanneh AHBLRD VANIDCR NIH HHSNIA NIH HHSNCRR NIH HHSNIAID NIH HHSNCI NIH HHSNIGMS NIH HHSNIH HHS111742https://www.ebi.ac.uk/biostudies/studies/S-EPMC9791981biostudies-literatureUnknown41(10)Crosstalk between metabolic and signaling events that induce tumor metastasis remains elusive. Here, we determine how oncogenic sphingosine 1-phosphate (S1P) metabolism induces intracellular C3 complement activation to enhance migration/metastasis. We demonstrate that increased S1P metabolism activates C3 complement processing through S1P receptor 1 (S1PR1). S1P/S1PR1-activated intracellular C3b-α'₂ is associated with PPIL1 through glutamic acid 156 (E156) and aspartic acid 111 (D111) residues, resulting in NLRP3/inflammasome induction. Inactivation mutations of S1PR1 to prevent S1P signaling or mutations of C3b-α'₂ to prevent its association with PPIL1 attenuate inflammasome activation and reduce lung colonization/metastasis in mice. Also, activation of the S1PR1/C3/PPIL1/NLRP3 axis is highly associated with human metastatic melanoma tissues and patient-derived xenografts. Moreover, targeting S1PR1/C3/PPIL1/NLRP3 signaling using molecular, genetic, and pharmacologic tools prevents lung colonization/metastasis of various murine cancer cell lines using WT and C3a-receptor1 knockout (C3aR1^-/-) mice. These data provide strategies for treating high-grade/metastatic tumors by targeting the S1PR1/C3/inflammasome axis.Cell reportsCrosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis.PMC9791981P30 CA138313P01 CA203628T32 AI132164R01 CA214461R21 CA104579T32 GM132055R01 CA236379R01 CA250458C06 RR015455IK6 BX005235P30 GM103339R56 AG069769S10 OD018113R56 AI119026T32 DE017551R01 DE016572R25 GM113278Ogretmen BLi HSheridan MLilly MOleinik NSaatci OSzulc ZAtkinson CAtilgan FCVoelkel-Johnson CPeterson YKMehrotra SNguyen HJanneh AHTomlinson SSahin OMarangoni EKassir MFLee HGfalseCrosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis.Crosstalk between metabolic and signaling events that induce tumor metastasis remains elusive. Here, we determine how oncogenic sphingosine 1-phosphate (S1P) metabolism induces intracellular C3 complement activation to enhance migration/metastasis. We demonstrate that increased S1P metabolism activates C3 complement processing through S1P receptor 1 (S1PR1). S1P/S1PR1-activated intracellular C3b-α'₂ is associated with PPIL1 through glutamic acid 156 (E156) and aspartic acid 111 (D111) residues, resulting in NLRP3/inflammasome induction. Inactivation mutations of S1PR1 to prevent S1P signaling or mutations of C3b-α'₂ to prevent its association with PPIL1 attenuate inflammasome activation and reduce lung colonization/metastasis in mice. Also, activation of the S1PR1/C3/PPIL1/NLRP3 axis is highly associated with human metastatic melanoma tissues and patient-derived xenografts. Moreover, targeting S1PR1/C3/PPIL1/NLRP3 signaling using molecular, genetic, and pharmacologic tools prevents lung colonization/metastasis of various murine cancer cell lines using WT and C3a-receptor1 knockout (C3aR1^-/-) mice. These data provide strategies for treating high-grade/metastatic tumors by targeting the S1PR1/C3/inflammasome axis.2022-01-01T00:00:00Z2022 Dec2026-06-01T02:21:49.781Z2025-04-04T00:16:14.413ZS-EPMC97919813647687310.1016/j.celrep.2022.111742