TOMOGRAPHY, June 2016, Volume 2, Issue 2: 146-157
Imaging Sensitivity of Quiescent Cancer Cells to Metabolic Perturbations in Bone Marrow Spheroids
1Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, Michigan; 2Biointerfaces Institute, University of Michigan College of Engineering, Ann Arbor, Michigan; 3Department of Radiology, Center for Molecular Imaging, University of Michigan Medical School, Ann Arbor, Michigan; 4Department of Macromolecular Science and Engineering, University of Michigan College of Engineering, Ann Arbor, Michigan; and 5Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan
Malignant cells from breast cancer, as well as other common cancers such as prostate and melanoma, may persist in bone marrow as quiescent, nondividing cells that remain viable for years or even decades before resuming proliferation to cause recurrent disease. This phenomenon, referred to clinically as tumor dormancy, poses tremendous challenges to curing patients with breast cancer. Quiescent tumor cells resist chemotherapy drugs that predominantly target proliferating cells, limiting success of neoadjuvant and adjuvant therapies. We recently developed a 3-dimensional spheroid model of quiescent breast cancer cells in bone marrow for mechanistic and drug testing studies. We combined this model with optical imaging methods for label-free detection of cells, preferentially using glycolysis versus oxidative metabolism to investigate the metabolic state of co-culture spheroids with different bone marrow stromal and breast cancer cells. Through imaging and biochemical assays, we identified different metabolic states of bone marrow stromal cells that control metabolic status and flexibilities of co-cultured breast cancer cells. We tested metabolic stresses and targeted inhibition of specific metabolic pathways to identify approaches to preferentially eliminate quiescent breast cancer cells from bone marrow environments. These studies establish an integrated imaging approach to analyze metabolism in complex tissue environments to identify new metabolically targeted cancer therapies.