Date of Award

2024

Embargo Period

2-12-2029

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

Ozlem Yilmaz

Third Advisor

Melinda Engevik

Fourth Advisor

Jessica Hartman

Fifth Advisor

Joe Delaney

Abstract

Advancements in cancer therapies and early detection have allowed mortality rates for many cancers to drop or remain consistent over the past 30 years. Contrary to broad improvements in the treatment and incidence of head and neck cancers overall, oral squamous cell carcinoma (OSCC), particularly of the base of the tongue, has been increasing in prevalence. Considering the low five-year survival rate and high recurrence and metastasis of this cancer type, identification of novel patient subgroups and unknown risk factors is needed. Porphyromonas gingivalis (P. gingivalis) is a gram-negative, asaccharolytic anaerobe that resides in the oral cavity. P. gingivalis is notable as the keystone pathogen for adult periodontitis, and for its ability to invade human primary gingival epithelial and endothelial cells to evade immune clearance and successfully replicate within host cells, persisting as a chronic infection. Notably, P. gingivalis has been reported to occur at a higher concentration in OSCC tissue compared to adjacent normal gingiva. The severity of OSCC mortality was also correlated with serum antibody levels to P. gingivalis and periodontal disease progression. These reports indicate that P. gingivalis may be an additional risk factor influencing the severity and development of OSCC in patients. OSCC have been shown to downregulate ceramide synthase 1, which produces the signaling sphingolipid, C18-ceramide. C18-ceramide is key in initiating LC3B-mediated lethal mitophagy and tumor suppression, often induced by chemotherapeutic and radiotherapeutic cancer treatment. Treatment of OSCC cells and orthotopic tumors with a C18-ceramide analogue drug to potently induce mitophagic stress has revealed that P. gingivalis infected cells exhibit inhibited lethal mitophagy. It was found that P. gingivalis disrupts the LC3B-ceramide complex to repress lethal mitophagy induced by various drugs by utilizing major fimbriae A (FimA). This is accomplished through novel binding of FimA to ANXA2, which prevents ANXA2-ceramide association involving E142 residue of ANXA2. By disrupting ANXA2 association with ceramide, the ANXA2-ceramide-LC3B complex that induces lethal mitophagy is also inhibited by P. gingivalis. A FimA-deleted mutant variant of P. gingivalis was unable to repress ceramide-dependent mitophagy. In addition, 16S rRNA sequencing of orthotopic OSCC tumors revealed that P. gingivalis induced changes to the tumor microbiome in response to LCL768 treatment, elevating the abundance of Gordonia, Stenotrophomonas, and Herbaspirillum. This study reveals that P. gingivalis assists OSCC survival through inhibition of ceramide-dependent lethal mitophagy. New targets for possible therapeutic targeting, such as FimA, have been identified to improve treatment response in OSCC tumors infected with P. gingivalis.

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Available for download on Monday, February 12, 2029

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