The Role of Non-Cell Autonomous Wnt Activation in Hair Follicle Growth and Cancer

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DESCRIPTION (provided by applicant): Tissue homeostasis and regeneration are mediated by the coordinated growth of multiple cell types to generate tissue that sustains integrity and function of the organism. This ability to durably regenerate tissue relies on adult stem cells that reside in a specialized environment called the niche, which influences their self- renewal, growth and differentiation. Failure to maintain or mobilize stem cells results in tissue loss and dysfunction, while uncontrolled activation of these cells can fuel disorganized growth and cancer. Elucidating how key molecular signals govern stem cell behavior holds tremendous implications for designing targeted therapies to treat human diseases. A major challenge to examining how mammalian stem cells are regulated is the inability of conventional static analysis to follow the fate and behavior of cell populations in vivo over time. This proposal aims to address a major gap in our knowledge of how signals can engage a population of undifferentiated cells to yield robust and organized growth. In particular, is still unclear (1) wht cellular behaviors such as cell divisions and movement are regulated by key morphogenetic signals during regeneration, (2) how these signals are disseminated throughout a field of cells in to ensure robust but compartmentalized growth, and (3) how these mechanisms can contribute to disorganized and uncontrolled growth during tumorigenesis. The hair follicle is the ideal model to address these questions as it is exceptionally accessible and undergoes well-characterized cyclical regeneration in a manner dependent on resident stem cells. By coupling this model to a novel live imaging technique we are now uniquely poised to address these outstanding questions. In this project, we examine how Wnt/�-catenin signaling, a key molecular pathway required for hair follicle regeneration, is propagated throughout a population of undifferentiated cells to promote synchronous and coordinated growth. By live imaging, we have found that only a subset of cells is required to fuel the non-cell autonomous activation of this signal and growth behaviors throughout surrounding epithelial cells and is associated with upregulation of diffusible Wnt ligands. Our first aim uses both in vitro cell culture and genetic mouse models that activate �-catenin in the presence or absence of Wnt secretion to determine the requirement for Wnt ligand secretion in promoting hair follicle regeneration. The second examines if Wnt secretion is required for epithelial Wnt activation in basal cell carcinomas (BCCs), the most common human skin cancer, which is dependent upon Wnt signaling for growth. We will also determine how sustained epithelial Wnt signaling can influence the mesenchyme to regulate BCC growth, using tissue grafting and genetic approaches to modulate epithelial and dermal Wnt activation in a BCC mouse model. Accomplishing these aims will provide novel insight into the principle mechanisms that ensure proper tissue regeneration and how they can also be exploited deleteriously to promote collective growth in cancer.