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Novel Small-Molecule CX3CR1 Antagonist Impairs Metastatic Seeding and Colonization of Breast Cancer Cells Fei Shen1, Yun Zhang1, Danielle L

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Novel Small-Molecule CX3CR1 Antagonist Impairs Metastatic Seeding and Colonization of Breast Cancer Cells Fei Shen1, Yun Zhang1, Danielle L Published OnlineFirst March 21, 2016; DOI: 10.1158/1541-7786.MCR-16-0013 Cell Death and Survival Molecular Cancer Research Novel Small-Molecule CX3CR1 Antagonist Impairs Metastatic Seeding and Colonization of Breast Cancer Cells Fei Shen1, Yun Zhang1, Danielle L. Jernigan1, Xin Feng1, Jie Yan2, Fernando U. Garcia2, Olimpia Meucci1, Joseph M. Salvino1, and Alessandro Fatatis1,2,3 Abstract Recent evidence indicates that cancer cells, even in the models of seeding and established metastasis. Importantly, coun- absence of a primary tumor, recirculate from established sec- teracting CX3CR1 activation impairs the lodging of circulating ondary lesions to further seed and colonize skeleton and soft tumor cells to the skeleton and soft-tissue organs and also neg- tissues, thus expanding metastatic dissemination and precipi- atively affects further growth of established metastases. Further- tating the clinical progression to terminal disease. Recently, we more, nine genes were identified that were similarly altered by reported that breast cancer cells utilize the chemokine receptor JMS-17-2 and CRISPRi and could sustain CX3CR1 prometastatic CX3CR1 to exit the blood circulation and lodge to the skeleton activity. In conclusion, these data support the drug development of experimental animals. Now, we show that CX3CR1 is over- of CX3CR1 antagonists, and promoting their clinical use will expressed in human breast tumors and skeletal metastases. To provide novel and effective tools to prevent or contain the pro- assess the clinical potential of targeting CX3CR1 in breast gression of metastatic disease in breast cancer patients. cancer, a functional role of CX3CR1 in metastatic seeding and progression was first validated using a neutralizing antibody Implications: This work conclusively validates the instrumental for this receptor and transcriptional suppression by CRISPR role of CX3CR1 in the seeding of circulating cancer cells and is interference (CRISPRi). Successively, we synthesized and char- expected to pave the way for pairing novel inhibitors of this acterized JMS-17-2, a potent and selective small-molecule receptor with current standards of care for the treatment of breast antagonist of CX3CR1, which was used in preclinical animal cancer patients. Mol Cancer Res; 14(6); 518–27. Ó2016 AACR. Introduction function as reservoirs of circulating tumor cells (CTC), which have been recently shown to cross-seed existing metastatic lesions as More than 90% of breast cancer patients are diagnosed with well as additional skeletal sites and soft-tissue organs (3, 4). By localized or regionally confined tumors, which are successfully egressing the peripheral blood and invading the surrounding treated by a combination of surgery and radiation. However, up to tissues, CTCs convert into disseminated tumor cells (DTC) that 30% of patients will eventually present distant recurrences (1), initiate secondary tumors. Therefore, interfering with the conver- which primarily affect bones, lungs, liver, and brain and remain sion of CTCs into DTCs would have the potential to prevent incurable, resulting in 40,000 annual deaths in the United States metastatic disease or significantly delay its progression (5). Unfor- alone. Notably, the skeleton is the first site of recurrence in at least tunately, clinical strategies directed to block cancer cells from half of the metastatic patients (2). These secondary bone tumors spreading are undeveloped, largely due to limited molecular targets and a lack of suitable pharmacologic or biologic thera- peutics. Studies from our laboratory and others indicate that 1Department of Pharmacology and Physiology, Drexel University Col- lege of Medicine, Philadelphia, Pennsylvania. 2Pathology and Labo- the chemokine receptor CX3CR1 drives cancer cells to the skeleton ratory Medicine, Drexel University College of Medicine, Philadelphia, (6, 7), activates prosurvival signaling pathways in normal (8) and Pennsylvania. 3The Biology of Prostate Cancer Program, Sidney Kim- cancer cells, promotes cell viability (9, 10), and therefore bears mel Cancer Center, Philadelphia, Pennsylvania. unique therapeutic potential (11). Fractalkine (FKN, also known Note: Supplementary data for this article are available at Molecular Cancer as CX3CL1; ref. 12), the sole chemokine ligand of CX3CR1, exists Research Online (http://mcr.aacrjournals.org/). as a transmembrane protein with strong adhesive properties and Current address for Y. Zhang: Shanghai Hengrui Pharmaceutical Co., 279 can be cleaved into a soluble molecule with potent chemoattrac- Wenjing Rd., Minhang District, Shanghai 200245, China. tant properties (13). We previously reported that FKN is consti- Corresponding Author: Alessandro Fatatis, Department of Pharmacology and tutively expressed by endothelial and stromal cells of the human Physiology and Department of Pathology and Laboratory Medicine, Drexel bone marrow both as membrane-anchored and -soluble forms th University College of Medicine, 245 North 15 Street, MS488, New College (14). Thus, functional interactions between FKN and its receptor Building Room 8211, Philadelphia, PA 19102. Phone: 215-762-8534; Fax: 215-762- are distinctively capable of mediating adhesion and extravasation 2299; E-mail: [email protected] of CX3CR1-expressing CTCs at the skeletal level, as well as doi: 10.1158/1541-7786.MCR-16-0013 supporting tumor colonization and progression in secondary Ó2016 American Association for Cancer Research. organs. 518 Mol Cancer Res; 14(6) June 2016 Downloaded from mcr.aacrjournals.org on September 29, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst March 21, 2016; DOI: 10.1158/1541-7786.MCR-16-0013 Targeting CX3CR1 Reduces Breast Cancer Metastasis Materials and Methods biochem), protease inhibitor cocktail (Calbiochem), and Ige- pal CA-630 (Sigma-Aldrich). Protein concentrations of cellular Cell lines and cell cultures lysates were determined using a BCA protein assay (Pierce). MDA-MB-231 (MDA-231) and SKBR3 human breast cancer cell Samples containing equivalent amounts of protein were lines were purchased from ATCC and cultured in DMEM (Invi- resolved by SDS-PAGE using 10% polyacrylamide gels and trogen) and McCoy's 5A (Invitrogen), respectively, containing then transferred onto Immobilon PVDF Membranes (Milli- 10% FBS (HyClone) and 0.1% gentamicin (Invitrogen). Starting pore Corporation). Membranes were blocked for one hour at from the original vials from ATCC, each cell line was expanded room temperature with 0.1% Tween 20/TBS with 5% (w/v) and frozen in different aliquots that were used for not more than powdered milk. Human CX3CR1 was detected using a primary 10 passages and not longer than 2 months following resuscita- rabbit polyclonal antibody (TP-502, Torrey Pines Biolabs) tion. Each cell line was genetically engineered to stably express used at 0.5 mg/mL, whereas the activation of the ERK signaling GFP by transduction with a proprietary lentiviral vector pathway was detected with rabbit phospho-ERK and total-ERK (Addgene) in DMEM for 24 hours. antibodies (Cell Signaling Technology) at 10 ng/mL. Primary antibodies were diluted in 0.1% Tween 20/TBS and incubated Clinical samples, IHC, and digital image analysis overnight at 4C. A secondary, HRP-conjugated antibody fi Deidenti ed human tissue specimens from primary breast (Pierce) was used at 10 ng/mL. Blotted membranes were tumors and bone metastatic lesions from breast cancer patients processed with SuperSignal Femto chemiluminescence sub- were obtained from the archives of the Department of Pathology strates (Pierce) and visualized using a FluorChem imaging at Drexel University College of Medicine (Philadelphia, PA). system (ProteinSimple). Immunohistochemical detection of breast adenocarcinoma mar- kers in primary tumors and CX3CR1 in bone metastases was Chemotaxis assay conducted using a BenchMark ULTRA module (Ventana Medical MDA-231 cells (1 Â 105) were starved overnight and plated Systems) with the following protocol: antigen retrieval (pH 8.1) in the top chamber of transwell inserts (filters with 8-mmpore using CC1 reagent 64 minutes, followed by primary antibody diameter; BD Falcon) 200 ml of serum-free culture medium. The incubation for 40 minutes at 37 C, and then staining with the XT, inserts were transferred into a 24-well plate, where each well ultraView Universal DAB Detection Kit (Ventana Medical Sys- contained 700 mL of serum-free medium with or without tems). We used primary antibodies against estrogen receptor (ER; recombinant human FKN (50 nmol/L; R&D Systems). Positive clone: SP1), progesterone receptor (PR; clone: 1E2), and HER2 controls were obtained using 10% FBS. For experiments involv- (clone: 4B5) from Ventana Medical Systems and diluted 1:50 on ing JMS-17-2 and the CX3CR1-neutralizing antibody (Torrey formalin-fixed paraffin-embedded sections. For the detection of Pines Biolabs), cells were plated on the upper side of the filters CX3CR1 in human primary tumors and metastases, we used a in serum-free medium containing JMS-17-2 (1 nmol/L, 10 primary antibody from Abcam CX3CR1 (ab802) as follows: nmol/L, and 100 nmol/L) or the antibody (15 mg/mL) and sections were deparaffinized for 30 minutes using a Xylene thentransferredtowellscontainingJMS-17-2ortheneutral- Substitute (Thermo Scientific), followed by rehydration in an izing antibody plus FKN. Cells were allowed to migrate at 37C ethanol gradient. Antigen retrieval was performed by heating the for6hours,andattheendoftheassay,thecellsstillonthetop sections at 95
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