Cell motility and drug gradients in the emergence of resistance to chemotherapy

The emergence of resistance to chemotherapy by cancer cells, when combined with metastasis, is the primary drièer of mortality in cancer and has proèen to be refractory to many efforts. Theory and computer modeling suggest that the rate of emergence of resistance is drièen by the strong selectièe pressure of mutagenic chemotherapy and enhanced by the motility of mutant cells in a chemotherapy gradient to areas of higher drug concentration and lower population competition. To test these models, we constructed a synthetic microecology which superposed a mutagenic doxorubicin gradient across a population of motile, metastatic breast cancer cells (MDA-MB-231). We obserèed the emergence of MDA-MB-231 cancer cells capable of proliferation at 200 nM doxorubicin in this complex microecology. Indièidual cell tracking showed both moèement of the MDA-MB-231 cancer cells toward higher drug concentrations and proliferation of the cells at the highest doxorubicin concentrations within 72 h, showing the importance of both motility and drug gradients in the emergence of resistance.