Cancer SCs (CSCs) are regarded as a source of heterogeneous tumor cells and are responsible for tumor initiation, metastasis, recurrence and therapy resistance. Although CSCs are somewhat similar to tissue SCs in that they are self-renewing, rare cell populations, their origin is still uncertain.
Accumulating evidence indicates that CSCs originate from SCs, progenitor cells or differentiated cells. However, these models have not been experimentally tested. It is possible that differentiated cells can benconverted into progenitor cells or CSCs during tumorigenesis, similar to the cell dedifferentiation that has been observed in haematopoietic systems.
In the new study, researchers found that the proliferating cell nuclear antigen-associated factor (PAF)-Wnt signalling axis converts normal epithelial cells into CSC-like (CSL) cells.
PAF was initially identified as a proliferating cell nuclear antigen interacting protein. PAF modulates translesion DNA synthesis, a DNA bypass process, by facilitating the switch of the translesion DNA synthesis polymerase.
In recent times, researchers found that PAF, as a co-factor of b-catenin transcriptional complex, positively modulates Wnt signalling. In this study, the results revealed that PAF is highly expressed in breast cancer cells and plays key roles in inducing mammary epithelial cell (MEC) plasticity and maintaining breast cancer cell stemness.
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 signalling. 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. These results unveil an unsuspected role of the PAF-Wnt signalling axis in modulating cell plasticity, which is required for the maintenance of breast cancer cell stemness.