Date of Award

Spring 5-21-2023

Embargo Period

5-21-2024

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry and Molecular Biology

College

College of Graduate Studies

First Advisor

Besim Ogretmen

Second Advisor

Michael Ostrowski

Third Advisor

Shikhar Mehrotra

Fourth Advisor

Christina Voelkel Johnson

Fifth Advisor

Joseph Delaney

Abstract

The tumor microenvironment (TME) is composed of complex constituents that consistently change to support tumor escape from anti-tumor immune surveillance, thus promoting cancer progression and negatively impacting patient survival. Components of the tumor microenvironment must have a reciprocal relationship with the cancer cells to allow tumors to escape the immune system. The functional roles of sphingolipid metabolism and the activating components of the complement system sustained in the tumor microenvironments represent an intricate mechanism that favors tumor growth and survival. 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-a’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-a’2 to prevent its association with PPIL1 attenuate inflammasome activation and reduce lung colonization/metastasis in mice. Also, the S1PR1/C3/PPIL1/NLRP3 axis activation 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 wild-type and C3a-receptor1 knockout (C3aR1-/-) mice. These data provide strategies for treating high-grade/metastatic tumors by targeting the S1PR1/C3/inflammasome axis.

Rights

Copyright is held by the author. All rights reserved.

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