A usable model of "decathlon winner" cancer cells in triplenegative breast cancer: Survival of resistant cancer cells in quiescence

We previously described a strategy for selecting highly adaptable rare triplenegative breast cancer (TNBC) cells based on their ability to survive a severe and prolonged metabolic challenge, e.g., a lack of glutamine. We hypothesized that metabolically adaptable (MA) cancer cells selected from the SUM149 cell line in this manner have the capacity to survive a variety of challenges that postulated "decathlon winner" cancer cells must survive to succeed in metastasis. These MA cells were resistant to glutaminase inhibitor CB-839, as predicted from their ability to proliferate without exogenous glutamine. They were also resistant to hypoxia, surviving treatment with hypoxia inducer cobalt chloride. Investigating the nature of intrinsic resistance in SUM149-MA cells, we found that 1-2 mM metformin completely inhibited the emergence of MA colonies in SUM149 cells in glutamine-free medium. These highly resistant MA cells grew into colonies upon removal of metformin, indicating that they survived in quiescence for several weeks under metformin treatment. This approach of selecting resistant cells worked equally well with additional TNBC cell lines, specifically inflammatory breast cancer cell line FC-IBC02 and mouse breast cancer cell line 4T07. In both cases, less than 1% of cells survived metformin treatment and formed colonies in glutamine-free medium. The MA cells selected in this manner were significantly more resistant to the chemotherapeutic drug doxorubicin than the parental cell lines. We conclude that our approach may be useful in developing usable models of cancer cell quiescence and therapy resistance in TNBC.