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

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^*

^*Corresponding author for this work

Surgery

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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.

Original language	English (US)
Article number	111742
Journal	Cell reports
Volume	41
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2022.111742
State	Published - Dec 6 2022

Funding

We thank the members of the Ogretmen Laboratory for their technical support and helpful discussions. This work was supported by research funding from the National Institutes of Health ( AG069769 , CA214461 , CA214461-S1 , DE016572 , and P01 CA203628 ) and the National Institute of General Medical Sciences (NIGMS) T32 training grant ( T32GM132055 ). The core facilities utilized are supported by NIH ( C06 RR015455 ), Hollings Cancer Center Support grant ( P30 CA138313 ), or Center of Biomedical Research Excellence (Cobre) in Lipidomics and Pathobiology ( P30 GM103339 ). In addition, the Zeiss 880 microscope was funded by a Shared Instrumentation grant ( S10 OD018113 ). This study was performed in accordance with the guidelines in the Guide for the Care and the Use of Laboratory Animals of the National Institutes of Health. All the animals were handled according to the approved Institutional Animal Care and Use Committee (IACUC) protocol (2018-00412) of the Medical University of South Carolina. We thank the members of the Ogretmen Laboratory for their technical support and helpful discussions. This work was supported by research funding from the National Institutes of Health (AG069769, CA214461, CA214461-S1, DE016572, and P01 CA203628) and the National Institute of General Medical Sciences (NIGMS) T32 training grant (T32GM132055). The core facilities utilized are supported by NIH (C06 RR015455), Hollings Cancer Center Support grant (P30 CA138313), or Center of Biomedical Research Excellence (Cobre) in Lipidomics and Pathobiology (P30 GM103339). In addition, the Zeiss 880 microscope was funded by a Shared Instrumentation grant (S10 OD018113). This study was performed in accordance with the guidelines in the Guide for the Care and the Use of Laboratory Animals of the National Institutes of Health. All the animals were handled according to the approved Institutional Animal Care and Use Committee (IACUC) protocol (2018-00412) of the Medical University of South Carolina. Conception and design, A.H.J. and B.O.; methodology development, A.H.J. M.F.K. F.C.A. H.G.L. M.S. N.O. Z.S. C.V.-J. H.N. C.A. S.T. and B.O.; data acquisition, A.H.J. M.F.K. F.C.A. N.O. Y.K.P. E.M. O. Saatci, O. Sahin, and B.O.; data analysis and interpretation, A.H.J. H.L. Y.K.P. O. Saatci, O. Sahin, M.L. C.A. S.T. S.M. and B.O.; manuscript writing, review, and revision, A.H.J. and B.O.; administrative, technical, or material support, A.H.J. and B.O.; study supervision, B.O. The authors declare no competing interests. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science.

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2022.111742

Cite this

Janneh, A. H., Kassir, M. F., Atilgan, F. C., Lee, H. G., Sheridan, M., Oleinik, N., Szulc, Z., Voelkel-Johnson, C., Nguyen, H., Li, H., Peterson, Y. K., Marangoni, E., Saatci, O., Sahin, O., Lilly, M., Atkinson, C., Tomlinson, S., Mehrotra, S., & Ogretmen, B. (2022). Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis. Cell reports, 41(10), Article 111742. https://doi.org/10.1016/j.celrep.2022.111742

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title = "Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis",

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.",

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author = "Janneh, {Alhaji H.} and Kassir, {Mohamed Faisal} and Atilgan, {F. Cansu} and Lee, {Han Gyul} and Megan Sheridan and Natalia Oleinik and Zdzislaw Szulc and Christina Voelkel-Johnson and Hung Nguyen and Hong Li and Peterson, {Yuri K.} and Elisabetta Marangoni and Ozge Saatci and Ozgur Sahin and Michael Lilly and Carl Atkinson and Stephen Tomlinson and Shikhar Mehrotra and Besim Ogretmen",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = dec,

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doi = "10.1016/j.celrep.2022.111742",

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Janneh, AH, Kassir, MF, Atilgan, FC, Lee, HG, Sheridan, M, Oleinik, N, Szulc, Z, Voelkel-Johnson, C, Nguyen, H, Li, H, Peterson, YK, Marangoni, E, Saatci, O, Sahin, O, Lilly, M, Atkinson, C, Tomlinson, S, Mehrotra, S & Ogretmen, B 2022, 'Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis', Cell reports, vol. 41, no. 10, 111742. https://doi.org/10.1016/j.celrep.2022.111742

TY - JOUR

T1 - Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis

AU - Janneh, Alhaji H.

AU - Kassir, Mohamed Faisal

AU - Atilgan, F. Cansu

AU - Lee, Han Gyul

AU - Sheridan, Megan

AU - Oleinik, Natalia

AU - Szulc, Zdzislaw

AU - Voelkel-Johnson, Christina

AU - Nguyen, Hung

AU - Li, Hong

AU - Peterson, Yuri K.

AU - Marangoni, Elisabetta

AU - Saatci, Ozge

AU - Sahin, Ozgur

AU - Lilly, Michael

AU - Atkinson, Carl

AU - Tomlinson, Stephen

AU - Mehrotra, Shikhar

AU - Ogretmen, Besim

PY - 2022/12/6

Y1 - 2022/12/6

N2 - 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.

AB - 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.

KW - complement signaling

KW - CP: Cancer

KW - CP: Metabolism

KW - inflammasome

KW - metastasis

KW - S1P

KW - S1P receptor 1

KW - S1PR1

KW - sphingolipids

KW - sphingosine 1-phosphate

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DO - 10.1016/j.celrep.2022.111742

M3 - Article

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JO - Cell reports

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

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ASJC Scopus subject areas

UN SDGs

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