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Dissertation
Mechanistic role of CX3CR1 surface expression in driving metastatic progression of prostate cancer
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2026
DOI:
https://doi.org/10.17918/00011537
Abstract
Metastatic prostate cancer remains largely incurable, and a better understanding of the cellular mechanisms that support metastatic progression is needed to develop more effective therapeutic strategies. Previous work from our laboratory identified CX3CR1-expressing prostate cancer cells as a rare subpopulation with metastasis-initiating properties. However, the biological features that distinguish CX3CR1 surface-positive cells and support their metastatic function remain incompletely understood. This dissertation investigated the metabolic, microenvironmental, and therapeutic significance of CX3CR1 surface expression in prostate cancer progression. Using CX3CR1 surface staining, we identified distinct CX3CR1Surf− and CX3CR1Surf+ populations in PC3-ML prostate cancer cells. CX3CR1Surf+ cells were enriched in metastatic lesions compared with in vitro culture, supporting the association between CX3CR1 surface expression and metastatic progression. Metabolic analysis revealed that CX3CR1Surf+ cells display reduced oxidative phosphorylation and increased glycolytic activity at baseline. Stimulation with CX3CL1/fractalkine further altered metabolism specifically in CX3CR1Surf+ cells, suggesting that ligand-dependent CX3CR1 signaling may enhance the metabolic flexibility of this population. Unexpectedly, glycolytic enzyme analysis indicated reduced HKII expression in CX3CR1Surf+ cells and suggested that PC3-ML cells may rely more heavily on HKI for glucose catabolism. This dissertation also demonstrates that stromal cells stabilize the CX3CR1Surf+ population over time, suggesting that the metastatic microenvironment may help maintain, rather than simply induce, this cell state. Finally, pharmacological inhibition of CX3CR1 with FX-68 reduced metastatic tumor burden in vivo and was associated with increased tumor cell apoptosis without major effects on necrosis. Collectively, these findings support a model in which CX3CR1 surface expression identifies a plastic, metabolically distinct, stromally supported, and therapeutically targetable prostate cancer subpopulation that contributes to metastatic progression.
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Details
- Title
- Mechanistic role of CX3CR1 surface expression in driving metastatic progression of prostate cancer
- Creators
- Ruxu Zhai
- Contributors
- Joanne R. Mathiasen (Advisor)Alessandro Fatatis (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University
- Number of pages
- x, 164 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991022202459304721