Modeling differentiation-state transitions linked to therapeutic escape in triple-negative breast cancer

• DOI: 10.1371/journal.pcbi.1006840
• Publication Date: 2019-03-11T17:37:52Z
• Authors: Margaret P. Chapman; Tyler Risom; Anil J. Aswani; Ellen M. Langer; Rosalie C. Sears; Claire J. Tomlin
• Keywords: Triple-negative breast cancer

Drug resistance in breast cancer cell populations has been shown to arise through phenotypic transition of cells a drug-tolerant state, for example epithelial-to-mesenchymal or stem state. However, many tumors are heterogeneous mixture types with numerous epigenetic states addition stem-like and mesenchymal phenotypes, the dynamic behavior this response drug treatment is not well-understood. Recently, we showed that plasticity between differentiation states, as identified intracellular markers such cytokeratins, linked specific targeted therapeutics. Understanding dynamics differentiation-state transitions context could facilitate development more effective treatments cancers exhibit heterogeneity plasticity. In work, develop computational models drug-treated, phenotypically triple-negative (TNBC) line elucidate feasibility mechanism therapeutic escape tumor subtype. Specifically, use modeling predict changes underlie therapy-induced marker expression recently observed HCC1143 line. We report several statistically significant rates basal, luminal, mesenchymal, non-basal/non-luminal/non-mesenchymal populations. Moreover, validate model predictions on division death empirically, test our an independent data set. Overall, demonstrate induced by therapy can provoke distinct aggregations drug-resistant cells, which may be fundamental design improved regimens heterogeneity.