Date of Award

Spring 4-9-2025

Embargo Period

4-9-2030

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

Christina Voelkel-Johnson

Third Advisor

Michael Ostrowski

Fourth Advisor

Shikhar Mehrotra

Fifth Advisor

Ozgur Sahin

Abstract

Cancer metastasis remains the leading cause of cancer-related mortality, yet the molecular mechanisms driving this process are incompletely understood. Spinster Homolog 2 (SPNS2) is an important transporter exporting sphingosine-1-phosphate (S1P), a bioactive lipid that regulates cell migration, survival, and immune cell trafficking. Despite emerging evidence linking SPNS2 to tumor progression, conflicting reports suggest it may either promote or suppress metastasis depending on cellular context. This dissertation systematically investigates the role of SPNS2 in cancer metastasis and progression, addressing these discrepancies through an integrated approach combining clinical data analyses, molecular biology techniques, and preclinical models.

Kaplan–Meier analyses revealed that high SPNS2 expression is positively correlated with poor overall survival in breast, lung, ovarian, and pancreatic cancers, as well as enhanced lymphatic dissemination in breast cancer. SPNS2 overexpression in cancer cell lines promoted S1P export, activated the S1P receptor 1-AKT pathway, and induced EMT and cancer stemness, thereby increasing cell migration and lung metastasis. In contrast, SPNS2 knockout diminished S1P secretion, EMT, and cancer stemness, leading to impaired cell migration and lung metastasis. Additionally, immunophenotyping and transcriptomic analyses demonstrated that SPNS2 inhibition reprograms the tumor microenvironment by activating systemic anti-tumor immune responses mediated by T cells and myeloid cells, leading to reduced primary tumor growth and spontaneous lung metastases. Mechanistically, SPNS2 inhibition triggers immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs) that prime myeloid cells for antigen presentation and activate T cells to mount an effective anti-tumor response.

Notably, pharmacological inhibition using a novel small-molecule SPNS2 inhibitor (SLF82801178) recapitulated the effects observed with genetic ablation by suppressing primary tumor growth and lung metastasis while enhancing T cell-mediated anti-tumor responses. Therapeutic administration of the SPNS2 inhibitor following surgical resection of primary tumors significantly reduced distant metastatic burden, suggesting potential clinical utility in adjuvant settings.

Collectively, these findings establish SPNS2 as a pivotal regulator of cancer metastasis that functions through dual mechanisms, driving tumor cell-intrinsic pro-metastatic signaling and orchestrating an immunosuppressive tumor microenvironment. Targeting SPNS2 disrupts these processes and reconditions the immune landscape, offering a potential therapeutic strategy to curb metastatic progression and improve patient outcomes.

Rights

Copyright is held by the author. All rights reserved.

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Available for download on Tuesday, April 09, 2030

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