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Publication

Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis.

Cell reports | 2022

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.

Pubmed ID: 36476873 RIS Download

Research resources used in this publication

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Associated grants

Agency: NIDCR NIH HHS, United States
Id: T32 DE017551
Agency: NIGMS NIH HHS, United States
Id: T32 GM132055
Agency: NCI NIH HHS, United States
Id: P01 CA203628
Agency: NCI NIH HHS, United States
Id: R01 CA250458
Agency: NIGMS NIH HHS, United States
Id: P30 GM103339
Agency: NIDCR NIH HHS, United States
Id: R01 DE016572
Agency: NCI NIH HHS, United States
Id: R01 CA236379
Agency: NIA NIH HHS, United States
Id: R56 AG069769
Agency: NCI NIH HHS, United States
Id: R01 CA214461

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