Crosstalk Between Pro-Survival Sphingolipid Metabolism and Complement Signaling Induces Inflammasome-Mediated Tumor Metastasis
Year: 2022
Type: article
Abstract: Crosstalk between metabolic and signaling events that induce tumor metastasis remains elusive. Here, we determined how oncogenic sphingosine 1-phosphate (S1P) metabolism activates intracellular C3-complement molecules 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 was 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 attenuated inflammasome activation and reduced lung colonization/metastasis in mice. Also, activation of the S1PR1/C3/PPIL1/NLRP3 axis was highly associated with human metastatic melanoma tissues and patient-derived xenografts (PDXs). Moreover, targeting S1PR1/C3/PPIL1/NLRP3 signaling using molecular, genetic, and/or pharmacologic tools prevented lung colonization/metastasis of B16 melanoma-derived tumors using WT and C3a-receptor1 knockout (C3aR1-/-) mice. Overall, these data provide novel strategies for the treatment of high-grade/metastatic tumors by targeting the S1PR1/C3/inflammasome axis.
Source: Cell Reports
Authors: Alhaji H. Janneh, Mohamed Faisal Kassir, F. Cansu Atilgan, Han Gyul Lee, Megan Sheridan, Natalia Oleinik, Zdzislaw Szulc, Christina Voelkel-Johnson, Hung Nguyen, Hong Li, Yuri K. Peterson, Elisabetta Marangoni, Ozge Saatci, Ozgur Sahin, Michael Lilly, Carl Atkinson, Stephen Tomlinson, Shikhar Mehrotra, Besim Ogretmen
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: U.S. Department of Veterans Affairs, Medical University of South Carolina, National Institutes of Health, National Institute on Aging, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Dental and Craniofacial Research, National Center for Research Resources
Awards: G1007975022, G1250730630, G1436149861, G1702120599, G1793475525, EXTRAMURAL RESEARCH FACILITIEIS CONSTRUCTION, G2598401476, G2695058022, G3410771321, G3413486156, G346819144, Confocal/Multiphoton Microscope Upgrade, G4036850060, G5045962411, Complement inhibitors and immunotherapy, G6106915579, G6955708329, G8844758959, G8850684052, T-COHR: Training in Craniofacial and Oral Health Research, G922188526
OpenAlex ID: W4310860992