The research focus in my laboratory is to utilize functional genomic approaches to investigate the molecular regulation, and function(s) of the Wnt/β-catenin signaling pathway and in the context of animal development, stem cell regulation and disease, such as cancer. A major focus of the current research has been in the area of discovering novel Wnt-associated cancer therapeutics/small molecules that specifically, and potently target the activity of β-catenin-TCF driven transcription in cells exhibiting deregulated Wnt activity (Gonsalves et al., 2011; Narayanan et al., 2012; Lee et al., 2013). Observations made in these studies are revealing novel insights into the regulation of cancer and cancer stem cells (CSCs) by the Wnt pathway that we are investigating at present. We are also in the process of generating a screening platform for patient-derived xenograft (PDX) and 3D micro-tumor (sphere) models to assess the effect of combinatorial treatments of pathway-specific inhibitors and traditional chemotherapeutic drugs and radiotherapy. In addition, we have identified novel microRNA (miRNA) modifiers of the Wnt pathway that function at the level of modifying the activity of β-catenin and TCF, and play important roles in the regulation of male germline stem cell differentiation in the Drosophila model (Pancratov et al., 2013), and in growth/proliferation of human colon cancer cell lines (Anton et al., 2011). Along similar lines of investigation, we are interested in determining TCF-dependent versus TCF-independent functions of β-catenin in the regulation of self-renewal/differentiation in mouse and human embryonic stem cells (ESCs) as well as in CSCs (Faunes et al., 2013). Finally, my laboratory is engaged in the development of new molecular tools with therapeutic and/or prognostic applications that can be used to both modulate as well as monitor Wnt activity in patient-derived primary cells. In collaboration with Drs. Perrimon and Yeh at the Harvard Medical School, my lab has developed an FN3-scaffold based screen for β-catenin-interacting peptide aptamers (PAPTs), which can function as intracellular antibodies that can recognize protein targets of interest within a cell (Yeh, Gocha et al., 2013). We are currently validating the use of these β-cat-targeted PAPTs as both therapeutic agents and as novel biosensors to visualize the activity/sub-cellular localization of endogenous protein targets in vivo. The long-term goal of my lab is to generate a Wnt pathway-specific modulatory toolkit including small molecules, microRNAs, and PAPTs that can serve as targeted therapeutic/diagnostic reagents, as well as molecular tools to study the function of this critical signaling pathway in stem cell development and cancer.