title: Cell motility and drug gradients in the emergence of resistance to chemotherapy.
abstract: The emergence of resistance to chemotherapy by cancer cells, when combined with metastasis, is the primary driver of mortality in cancer and has proven to be refractory to many efforts. Theory and computer modeling suggest that the rate of emergence of resistance is driven by the strong selective 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 observed the emergence of MDA-MB-231 cancer cells capable of proliferation at 200 nM doxorubicin in this complex microecology. Individual cell tracking showed both movement 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.
authors.affiliation: Princeton Institute for the Science and Technology of Materials, Department of Electrical Engineering, Princeton University, Princeton, NJ 08544.
authors.forename: Amy
authors.initials: A
authors.lastname: Wu
authors.forename: Kevin
authors.initials: K
authors.lastname: Loutherback
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lambert
authors.forename: Luis
authors.initials: L
authors.lastname: Estévez-Salmerón
authors.forename: Thea D
authors.initials: TD
authors.lastname: Tlsty
authors.forename: Robert H
authors.initials: RH
authors.lastname: Austin
authors.forename: James C
authors.initials: JC
authors.lastname: Sturm
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D004317:Doxorubicin; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D019143:Evolution, Molecular; D006801:Humans; D046210:Microfluidic Analytical Techniques; D009369:Neoplasms / Q000503:physiopathology*; D012641:Selection, Genetic; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin
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