title: Modeling selective elimination of quiescent cancer cells from bone marrow.
abstract: Patients with many types of malignancy commonly harbor quiescent disseminated tumor cells in bone marrow. These cells frequently resist chemotherapy and may persist for years before proliferating as recurrent metastases. To test for compounds that eliminate quiescent cancer cells, we established a new 384-well 3D spheroid model in which small numbers of cancer cells reversibly arrest in G1/G0 phase of the cell cycle when cultured with bone marrow stromal cells. Using dual-color bioluminescence imaging to selectively quantify viability of cancer and stromal cells in the same spheroid, we identified single compounds and combination treatments that preferentially eliminated quiescent breast cancer cells but not stromal cells. A treatment combination effective against malignant cells in spheroids also eliminated breast cancer cells from bone marrow in a mouse xenograft model. This research establishes a novel screening platform for therapies that selectively target quiescent tumor cells, facilitating identification of new drugs to prevent recurrent cancer.
authors.affiliation: Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI 48109; Biointerfaces Institute, University of Michigan College of Engineering, Ann Arbor, MI 48109.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Cavnar
authors.affiliation: Department of Radiology, University of Michigan School of Medicine, Ann Arbor, MI 48109; Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rickelmann
authors.affiliation: Department of Radiology, University of Michigan School of Medicine, Ann Arbor, MI 48109; Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Kaille F
authors.initials: KF
authors.lastname: Meguiar
authors.affiliation: Department of Radiology, University of Michigan School of Medicine, Ann Arbor, MI 48109; Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Annie
authors.initials: A
authors.lastname: Xiao
authors.affiliation: Department of Radiology, University of Michigan School of Medicine, Ann Arbor, MI 48109.
authors.forename: Joseph
authors.initials: J
authors.lastname: Dosch
authors.affiliation: Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI 48109; Biointerfaces Institute, University of Michigan College of Engineering, Ann Arbor, MI 48109.
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Leung
authors.affiliation: Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI 48109; Biointerfaces Institute, University of Michigan College of Engineering, Ann Arbor, MI 48109.
authors.forename: Sasha
authors.initials: S
authors.lastname: Cai Lesher-Perez
authors.affiliation: Department of Radiology, University of Michigan School of Medicine, Ann Arbor, MI 48109; Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Shashank
authors.initials: S
authors.lastname: Chitta
authors.affiliation: Department of Radiology, University of Michigan School of Medicine, Ann Arbor, MI 48109; Department of Macromolecular Science and Engineering, University of Michigan College of Engineering, Ann Arbor, MI 48109.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Luker
authors.affiliation: Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI 48109; Biointerfaces Institute, University of Michigan College of Engineering, Ann Arbor, MI 48109; Department of Macromolecular Science and Engineering, University of Michigan College of Engineering, Ann Arbor, MI 48109.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Takayama
authors.affiliation: Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI 48109; Department of Radiology, University of Michigan School of Medicine, Ann Arbor, MI 48109; Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109. Electronic address: gluker@med.umich.edu.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Luker
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008163:Luminescent Measurements / Q000379:methods; D051379:Mice; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology*; D014410:Tumor Stem Cell Assay / Q000379:methods*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents