Abstract
Persistence is a transient state that poses an important health concern in cancer therapy. The mechanisms associated with persister phenotypes are highly diverse and complex, and many aspects of persister cell physiology remain to be explored. We applied a melanoma cell line and panel of chemotherapeutic agents to show that melanoma persister cells are not necessarily preexisting dormant cells; in fact, they may be induced by cancer chemotherapeutics. Our metabolomics analysis and phenotype microarray assays further demonstrated a transient upregulation in Krebs cycle metabolism in persister cells. We also verified that targeting electron transport chain activity can significantly reduce melanoma persister levels. The reported metabolic remodeling feature seems to be a conserved characteristic of melanoma persistence, as it has been observed in various melanoma persister subpopulations derived from a diverse range of chemotherapeutics. Elucidating a global metabolic mechanism that contributes to persister survival and reversible switching will ultimately foster the development of novel cancer therapeutic strategies.
Highlights
Conventional cancer therapies target the mechanisms underlying the rapid growth of tumor cells
Persister cells are defined as a small subpopulation of phenotypic variants that are transiently tolerant to drugs
Cells surviving GEM treatment were transferred to fresh medium, regrown, and retreated with GEM to verify the transient state of melanoma persister cells (Figure 1A)
Summary
Conventional cancer therapies target the mechanisms underlying the rapid growth of tumor cells These therapies are usually inefficient for small subpopulations of persister cancer cells that are in a transient “persistence state” (Sharma et al, 2010; Ramirez et al, 2016; Hangauer et al, 2017). This phenomenon resembles bacterial persistence, which is characterized by slow growth coupled with the ability to tolerate unusually high levels of drugs and has been documented across multiple tumor cell lines and in response to a variety of therapeutic challenges (Hangauer et al, 2017).
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