Dissertation
Targeting CX3CR1 with novel antagonists for breast cancer metastasis
Doctor of Philosophy (Ph.D.), Drexel University
May 2016
DOI:
https://doi.org/10.17918/00002070
Abstract
Recent evidence indicates that cancer cells, even in the absence of a primary tumor, recirculate from established secondary lesions by re-entering the blood circulation to further seed and colonize skeleton and soft-tissues (cross-seeding), thus precipitating the clinical progression to terminal disease. This study was undertaken to establish the implication of the chemokine receptor CX3CR1 in the seeding of breast Circulating Tumor Cells (CTCs). To this end, we first showed that CX3CR1 is overexpressed in all four main molecular subtypes of breast adenocarcinoma and in skeletal metastases. Next, the functional role of CX3CR1 in metastatic seeding and progression was validated in animal models of metastasis using a neutralizing antibody and transcriptional suppression by CRISPR-interference (CRISPRi). Successively, newly synthesized, potent and selective small-molecule antagonists of CX3CR1 were successfully used to impair the seeding of breast CTCs to skeleton and soft-tissue organs in animal models. Further pre-clinical studies showed that interfering with CX3CR1 with our novel small-molecule inhibitors or conditionally silencing the receptor by CRISPRi prevented the cross-seeding of existing metastases and also blocked their growth, suggesting an additional role of CX3CR1 in tumor progression. Transcriptome analyses of metastatic tissues collected by Laser Capture Microdissection and interrogated by Nanostring technology identified several cancer-related genes that could mechanistically sustain the effects of CX3CR1 on the expansion of metastatic tumors. In conclusion, this study supports the development of CX3CR1 antagonists and their clinical use as novel and effective therapeutics to prevent or contain the metastatic disease in breast cancer patients.
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Details
- Title
- Targeting CX3CR1 with novel antagonists for breast cancer metastasis
- Creators
- Fei Shen
- Contributors
- Alessandro Fatatis (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 162 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991021888941604721