Mass cytometry to decipher the mechanism of nongenetic drug resistance in cancer

Abstract

Nongenetic resistance has recently been described as a major impediment to effective cancer therapy. Nongenetic resistance is challenging to study since it occurs nonuniformly, even in cell lines, and can involve the interplay of multiple survival pathways. Until recently, no technology allowed measurement of largescale alterations in survival pathways with single-cell resolution. Mass cytometry, a flow-based technique in which the activation of up to 50 proteins can be measured simultaneously in single-cell, now provides the ability to examine nongenetic resistance on the functional level on a cell-by-cell basis. The application of mass cytometry, in combination with new bioinformatic techniques, will allow fundamental questions on nongenetic resistance to be addressed: Is resistance caused by selection of cells with a pre-existing survival phenotype or induction of a survival program? Which survival pathways are necessary for nongenetic resistance and how do they interact? Currently, mass cytometry is being used to investigate the mechanism of nongenetic resistance to TRAIL-induced apoptosis. The approaches being developed to understand resistance to TRAIL will likely be applied to elucidate the mechanisms of nongenetic resistance broadly and in the clinic.