Generation of cancer stem cell-like cells by cell plasticity
Cancer stem cells (CSCs) contribute to tumor heterogeneity, therapy resistance, and metastasis. However, the regulatory mechanisms of cancer cell stemness remain elusive. We identified PCNA-associated factor (PAF) as a key molecule that controls cancer cell stemness. PAF is highly expressed in breast cancer cells, but not in mammary epithelial cells (MECs). In MECs, ectopic expression of PAF induces anchorage-independent cell growth and breast CSC marker expression. In mouse models, conditional PAF expression induces mammary ductal hyperplasia. Moreover, PAF expression endows MECs with a self-renewing capacity and cell heterogeneity generation via Wnt signaling. Conversely, ablation of endogenous PAF induces the loss of breast cancer cell stemness. Further cancer drug repurposing approaches reveal that NVP-AUY922 downregulates PAF and decreases breast cancer cell stemness. Our results unveil an unsuspected role of the PAF-Wnt signaling axis in modulating cell plasticity, which is required for the maintenance of breast cancer cell stemness.