Impact of EMT-driven plasticity on phenotypic diversity dynamics under chemotherapy [spontaneous]

Triple negative breast cancer (TNBC) is the most lethal breast cancer subgroup, as lack of targeted therapies and drug resistance reduce survival rates. Cellular plasticity enables cells to adapt non-genetically and overcome therapeutic pressure, thereby embodying a critical clinical hurdle. The epithelial-mesenchymal transition (EMT) is an example of phenotypic reprogramming linked to plasticity, drug resistance and metastasis. However, its exact impact on population diversity under therapeutic pressure is unknown. Here, we used single cell transcriptomics to investigate phenotypic diversity dynamics upon drug treatment in two human in vitro models of TNBC plasticity. Overall design: We used 2D cultures of ME cells in which part of mammary epithelial (Epi) cells spontaneously converts to a mesenchymal (Mes) subpopulation upon oncogenic transformation by shTP53-HRASG12V-hTERT, of which a fraction displayed further phenotypic drift (InB) (32k cells). Single cell cloning experiments were performed for each of the 3 populations analyzed (Epi, Mes and InB). 2 different clones were used as replicates per population, and analyzed under two conditions : untreated (4 weeks) or treated (1 week untreated, followed by three weeks of doxorubicin treatment).