Significant evidence supports overlap of failed organogenesis control and tumorigenic process. Indeed, a central regulator of progenitor cell proliferation and organ size checkpoint, the Hippo/YAP signaling pathway, is frequently overexpressed in variety of human tumors. In the mouse epidermis, overexpression of Yap induces expansion of progenitor cells in the interfollicular epidermis (IFE). Human basal cell carcinoma (BCC) is a skin tumor originating from the IFE progenitor cells as a result of activated Hedgehog signaling. The capacity of the Hedgehog and Hippo pathways to induce proliferation of the IFE progenitor cells suggests that these two pathways could cooperate during a tumorigenic process. Indeed, The Hippo/Yap pathway was found to be an essential mediator of the Hedgehog-driven medulloblastoma progression. Nevertheless, interaction between the Hippo and Hedgehog signaling in BCC is completely unclear. Our preliminary experiments show that Yap is upregulated by active Hedgehog signaling and required for BCC pathogenesis. We hypothesize that the Hippo and Hedgehog pathways interact in the skin basal stem cell during BCC initiation and progression. Following specific aims will test our hypothesis: (1) To determine requirement of Hippo/YAP pathway in the Hedgehog-driven tumor; (2) to investigate a mechanism by which YAP promotes SmoM2-driven tumorigenesis. To interrogate our first specific aim, we will study in vivo dependence of SmoM2 and Ptch-induced BCC on Yap expression during tumor initiation or maintenance. Detailed macroscopic and microscopic analyses will be performed in resulting BCC tumors to delineate Hippo functions. The Yap proficient and Yap-null epidermis will be compared at multiple time points for BCC clonal evolution, proliferation, and apoptosis. In the specific aim 2, we will investigate Yap co-activato function with TEAD transcription factors and identify Yap-regulated gene signature in the SmoM2-driven BCC. Using cell lines with a reporter for each pathway, we will determine exact point of Hedgehog-Hippo crosstalk. Overall, our experimental approach will investigate dependence of BCC tumors on Yap expression and define a mechanistic role of Yap during the Hedgehog-induced tumorigenesis. Human BCC is the most common tumor type with continued increase in the incidence. The advanced BCC tumors are commonly resistant to the Hedgehog pathway antagonists in part due to cooperation of other pathways to support progression. Thus identification of interacting signaling molecules that potentiate Hedgehog-driven BCC pathogenesis has an enormous potential for the future of therapeutic intervention. A more comprehensive understanding of the Hippo and Hedgehog pathway interaction will uncover novel and biologically relevant therapeutic targets.
As the most common cancer worldwide, development and progression of basal cell carcinoma (BCC) is believed to be dependent upon cooperation of several signaling molecules. In this proposal we will investigate previously unexplored connection between the Hippo pathway and BCC pathogenesis. Our work has enormous potential to reveal novel and biologically relevant targets that could be explored for the future therapeutic development.
| Maglic, Dejan; Schlegelmilch, Karin; Dost, Antonella Fm et al. (2018) YAP-TEAD signaling promotes basal cell carcinoma development via a c-JUN/AP1 axis. EMBO J 37: |
