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Journal article
Novel Small-Molecule CX3CR1 Antagonist Impairs Metastatic Seeding and Colonization of Breast Cancer Cells
Molecular cancer research, v 14(6), pp 518-527
Jun 2016
PMID: 27001765
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Recent evidence indicates that cancer cells, even in the absence of a primary tumor, recirculate from established secondary lesions to further seed and colonize skeleton and soft tissues, thus expanding metastatic dissemination and precipitating the clinical progression to terminal disease. Recently, we reported that breast cancer cells utilize the chemokine receptor CX3CR1 to exit the blood circulation and lodge to the skeleton of experimental animals. Now, we show that CX3CR1 is overexpressed in human breast tumors and skeletal metastases. To assess the clinical potential of targeting CX3CR1 in breast cancer, a functional role of CX3CR1 in metastatic seeding and progression was first validated using a neutralizing antibody for this receptor and transcriptional suppression by CRISPR interference (CRISPRi). Successively, we synthesized and characterized JMS-17-2, a potent and selective small-molecule antagonist of CX3CR1, which was used in preclinical animal models of seeding and established metastasis. Importantly, counteracting CX3CR1 activation impairs the lodging of circulating tumor cells to the skeleton and soft-tissue organs and also negatively affects further growth of established metastases. Furthermore, nine genes were identified that were similarly altered by JMS-17-2 and CRISPRi and could sustain CX3CR1 prometastatic activity. In conclusion, these data support the drug development of CX3CR1 antagonists, and promoting their clinical use will provide novel and effective tools to prevent or contain the progression of metastatic disease in breast cancer patients.
This work conclusively validates the instrumental role of CX3CR1 in the seeding of circulating cancer cells and is expected to pave the way for pairing novel inhibitors of this receptor with current standards of care for the treatment of breast cancer patients. Mol Cancer Res; 14(6); 518-27. ©2016 AACR.
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Details
- Title
- Novel Small-Molecule CX3CR1 Antagonist Impairs Metastatic Seeding and Colonization of Breast Cancer Cells
- Creators
- Fei Shen - Drexel UniversityYun Zhang - Drexel UniversityDanielle L Jernigan - Drexel UniversityXin Feng - Drexel UniversityJie Yan - Drexel UniversityFernando U Garcia - Drexel UniversityOlimpia Meucci - Drexel UniversityJoseph M Salvino - Drexel UniversityAlessandro Fatatis - Drexel University
- Publication Details
- Molecular cancer research, v 14(6), pp 518-527
- Publisher
- American Association for Cancer Research (AACR)
- Grant note
- R21 CA178540 / NCI NIH HHS R01 DA032444 / NIDA NIH HHS R01 DA015014 / NIDA NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology; Civil, Architectural, and Environmental Engineering; Pathology (and Laboratory Medicine)
- Web of Science ID
- WOS:000379358400002
- Scopus ID
- 2-s2.0-84975057128
- Other Identifier
- 991019168476804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology
- Oncology