EMT-ciliary signaling in quasi-mesenchymal-stem-like cells drives therapeutic resistance and is a druggable vulnerability in triple-negative breast cancer

Cancer therapeutic resistance is mediated, in part, by phenotypic heterogeneity and the plasticity of tumor cells, the latter being enabled by Epithelial-Mesenchymal Transition (EMT). However, EMT in human cancer therapeutic response remain poorly understood. We developed patient-derived organoids (PDOs) from human triple-negative breast cancer (TNBC) and investigated their response to chemotherapy. We found that chemotherapy treatment kills the bulk of tumor cells in PDOs, but there is selective survival of malignant cells that had activated an EMT program, entered a quasi-mesenchymal, stem cell-like state and display primary cilia. We developed a family of small-molecule inhibitors of ciliogenesis and show that treatment with these inhibitors, or genetic ablation of primary cilia, is sufficient to suppress this chemoresistance via NF?B-induced cell death. We conclude that an EMT-ciliary signaling axis induces chemoresistance in quasi-mesenchymal stem-like cells to help tumors evade chemotherapy and represents a druggable vulnerability in human TNBC. Overall design: Cancer cells dissociated from tumor tissue samples were used to generate PDOs. PDOs were dissociated and cells were processed for scRNAseq. PDOs from two different patient samples were used in the study. Non-treated PDOs were analyzed. Additionally, PDOs treated with DMSO (control: CTL) or doxorubicin or taxol or Nao-3 were used in the study.