LAUSR

Cancer stem cells (CSCs) are responsible for minimal residual disease tumor relapse. Appearing as the optimal target for therapy, these cells are very difficult to target due to their ability to resist proapoptotic stimuli. In order to overcome this evolutionary stem cell property, elucidation of the mechanistic regulation of these survival pathways is crucial. Previously we identified the CSC population in our model of basal-like breast cancer. Using targeted therapies directed at the tumor-driving pathway (Wnt and Met), we have shown that tumors initially respond to this therapy; however, they quickly become resistant. We have now confirmed that the Hippo transducer, Yap, is active in Wnt-Met tumors. The activity in the CSC population was increased compared to that of bulk tumor cells, indicating that Yap could be an option for anti-CSC therapy. Based on this, we utilized an inhibitor of Yap, verteporfin (VP). Treatment of 3D cultured Wnt-Met cells with VP inhibited CSC survival, showing that Yap is essential for tumor initiation. qPCR analysis of treated, self-renewing spheres showed that Yap and Wnt control distinct sets of stem cell genes. Only combination treatments sufficiently inhibited these genes. We now investigate the relationship between Wnt and Yap to understand how they cooperate and to identify a targetable bottleneck between the two pathways. Citation Format: Hazel M. Quinn, Regina Vogel, Walter Birchmeier. YAP and cancer stem cells in basal-like breast cancer [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A12.