Dissertation
CX3CR1 identifies breast tumor-initiating cells and its antagonism impairs cancer cells reseeding, colonization and progression
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2019
DOI:
https://doi.org/10.17918/bjyq-y674
Abstract
Patients with advanced breast cancer succumb to metastatic disease, which is currently incurable. Our research group has identified the chemokine receptor CX3CR1 as a key driver of metastatic breast cancer due to its role in the seeding of Circulating Tumor Cells (CTCs) to the skeleton and the progression of metastatic lesions. This project was undertaken to determine (1) whether targeting CX3CR1 could increase the vulnerability of CTCs to therapy and also contain the spreading of existing metastases to additional organ-sites; (2) elucidate the role of CX3CR1 in sustaining tumor growth and determining tumor response to chemotherapy. For our experiments we used FX-68, a potent and selective small-molecule antagonist of CX3CR1 both in vitro and in clinically relevant animal models of metastatic seeding and progression. We found that FX-68 dramatically prevents breast CTCs from lodging to bone and soft-tissues, extending their exposure and cytotoxic response to chemotherapy as well as containing the metastasis-to-metastasis burden. Furthermore, we discovered that CX3CR1 confers stemness properties to breast cancer cells and its inhibition by FX-68 impairs tumor growth and increases the response to chemotherapeutics both in vitro and in vivo. Finally, our studies have identified a set of genes that are similarly altered in disseminated tumors and CTCs in response to CX3CR1 antagonism. This gene-set informs on the mechanistic underpinning of the anti-tumor effects of FX-68 and provide a pharmaco-dynamic marker of target engagement. Taken together, these results reveal novel functional roles for CX3CR1 and strongly underscore the therapeutic potential of interfering with this receptor.
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Details
- Title
- CX3CR1 identifies breast tumor-initiating cells and its antagonism impairs cancer cells reseeding, colonization and progression
- Creators
- Chen Qian - DU
- Contributors
- Paul McGonigle (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 185 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 9368; 991014632566904721