Abstract
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.
Highlights
Quiescent cancer cells are relatively insensitive to cytotoxic therapies and may contribute to late relapse even decades after initial diagnosis of disease [1,2,3]
To investigate relative effects of HS-5 and HS-27A stromal cells on quiescence or growth of triple-negative (ERϪ/PRϪ/Her2Ϫ) MDA-MB-231 cells, we varied the composition of the stromal environment and independently monitored the growth of cancer and stromal cells with stably expressed click beetle (CB)Green and CBRed luciferases, respectively
MDA-MB-231 co-cultures with untransformed primary human mesenchymal stem cells (MSCs) grew rapidly compared with HS-5 cells, suggesting that HS-27A cells represent the subtype of mesenchymal stromal cells typically enriched through in vitro isolation
Summary
Quiescent cancer cells are relatively insensitive to cytotoxic therapies and may contribute to late relapse even decades after initial diagnosis of disease [1,2,3]. Bone marrow is regarded as a major reservoir for quiescent cancer cells. One strategy toward eliminating quiescent cancer cells is to selectively target unique metabolic demands of these cells, a hallmark feature of cancer that may be exacerbated by hypoxia in bone marrow niches [10]. Understanding differences in metabolism between disseminated cancer cells and stromal cells in bone marrow and developing therapies by selectively targeting cancer metabolism offer the potential to eliminate quiescent cancer cells and prevent late recurrence of disease
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