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

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

doi:10.1016/j.celrep.2022.111742

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

Cell Rep. 2022 Dec 6;41(10):111742. doi: 10.1016/j.celrep.2022.111742.

Authors

Alhaji H Janneh¹, Mohamed Faisal Kassir¹, F Cansu Atilgan¹, Han Gyul Lee¹, Megan Sheridan¹, Natalia Oleinik¹, Zdzislaw Szulc¹, Christina Voelkel-Johnson², Hung Nguyen³, Hong Li⁴, Yuri K Peterson⁵, Elisabetta Marangoni⁶, Ozge Saatci⁷, Ozgur Sahin⁷, Michael Lilly⁸, Carl Atkinson³, Stephen Tomlinson³, Shikhar Mehrotra³, Besim Ogretmen⁹

Affiliations

¹ Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
² Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
³ Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
⁴ Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Public Health, College of Medicine, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
⁵ Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
⁶ Translational Research Department, Institut Curie, Paris, France.
⁷ Department of Drug Discovery and Biomedical Sciences, School of Pharmacy, University of South Carolina, Columbia, SC 29208, USA.
⁸ Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
⁹ Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA. Electronic address: ogretmen@musc.edu.

Abstract

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.

Keywords: CP: Cancer; CP: Metabolism; S1P; S1P receptor 1; S1PR1; complement signaling; inflammasome; metastasis; sphingolipids; sphingosine 1-phosphate.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Humans
Inflammasomes*
Melanoma*
Mice

Substances

Inflammasomes

Abstract

Publication types

MeSH terms

Substances

Grants and funding