Abstract 2247: Intracellular complement signaling plays a critical role in s1p/s1pr1 mediated inflammasome activation and tumor metastasis.

Abstract Sphingolipid metabolism, specifically sphingosine 1-phosphate (S1P), has been demonstrated to regulate cancer progression and metastasis. Our previous research showed that oncogenic S1P and S1P receptor 1 (S1PR1) signaling activated intracellular C3 complement processing to enhance migration/metastasis through inflammasome activation by the C3-PPIL1 complex. This study addressed how the S1PR1/C3 axis mediates inflammasome/NLRP3 activation in various solid tumors, including melanoma and triple-negative breast cancer (TNBC). To better understand the roles of S1PR1 and C3 in mouse mammary tumorigenesis and metastasis, we crossed the MMTV-Cre S1pr1fl/fl; MMTV-Cre or C3Tdt; MMTV-Cre mice with MMTV-PyMt expressing mice to generate S1pr1fl/fl; MMTV-Cre; MMTV-PyMt or C3Tdt; and MMTV-Cre; MMTV-PyMt (controls) animals. Our preliminary data show that silencing C3 and S1PR1 selectively in mammary tumors significantly reduces tumor burden in MMTV-PyMt mice, consistent with decreased inflammasome signaling. Mechanistically, our data also showed that PPIL1-C3 complex requires SNU13 to induce cell migration in response to S1P signaling by mediating the alternative splicing of various factors involved in activating NLRP3/inflammasome in metastatic tumors. These findings suggest that attenuation of the S1PR1/C3 and PPIL1-SNU13-inflammasome signaling inhibits cancer cell migration and metastasis. Citation Format: Salih Gencer, Alhaji H. Janneh, Natalia Oleinik, Charles Chalfant, Besim Ogretmen. Intracellular complement signaling plays a critical role in s1p/s1pr1 mediated inflammasome activation and tumor metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2247.