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Dissertation
CX3CR1 Phenotypic Plasticity in Prostate Cancer Metastasis
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2024
DOI:
https://doi.org/10.17918/00010572
Abstract
We have previously reported that subsets of cancer cells (4-8%) expressing the chemokine receptor CX3CR1 on their surface (CX3CR1Surf+) are endowed with stemness features and behave as metastasis-initiating cells (MICs) when grafted in mice. We show that prostate cancer cells lacking surface CX3CR1 (CX3CR1Surf-) can re-express CX3CR1 on their surface in vitro and re-acquire MIC potential in vivo. We also found that intracellular trafficking is responsible for the early phase of this CX3CR1 switch and is accompanied by a partial Epithelial-Mesenchymal Transition, thus indicating phenotypic plasticity. Our studies also revealed that the changes in CX3CR1 protein expression and its surface localization occur in a cyclical pattern. This unprecedented finding suggests that the CX3CR1 plasticity might be controlled by an autoregulatory feedback loop. Additional experiments showed that disseminated tumors in the skeleton and softtissue organs of mice grafted with human prostate cancer cells harbored higher percentages of CX3CR1Surf+ phenotypes, indicating a key role of the tissue microenvironment in promoting CX3CR1 plasticity. When cancer cells were harvested from metastatic tumors and re-plated in culture, the overall percentage of CX3CR1Surf+ phenotypes rapidly reverted to that of pre-grafting levels, thus suggesting the implication of epigenetic mechanisms. In conclusion, this study identifies novel phenotypic plasticity inducing the emergence of CX3CR1Surf+ cells with MIC properties, which are likely responsible for metastatic recurrence and support the development of CX3CR1 antagonists for therapeutic purposes.
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Details
- Title
- CX3CR1 Phenotypic Plasticity in Prostate Cancer Metastasis
- Creators
- Jieyi Zhang
- Contributors
- Edward J. Hartsough (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 148 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991021901914804721