The overall focus of research in the Waterman laboratory is to define the role of Wnt signaling in intestinal stem cells and colon cancer stem cells. We aim to understand how the Wnt signal transduction pathway directs cellular self-renewal, differentiation, proliferation, and migration activities in normal and disease settings. A major focus is on how LEF/TCFs, the transcription factors that mediate Wnt signaling, regulate gene programs such as metabolism, RNA processing, and cell motility, and in return, how these gene programs are used to remodel the microenvironment and influence cellular states. A multi-disciplinary approach of next-gen and scRNA sequencing, cell biology, biochemistry-mass spectrometry, genome-wide ‘omics, imaging (with the Laboratory for Fluorescence Dynamics), animal models (with Edwards laboratory), mathematical modeling and systems biology (in collaboration with the Lowengrub and Lander groups) as we realize that complex features are best understood through collaborations. Using data from these collaborations, we probe how these gene expression patterns play out in 3D – in living systems (cultured cells, spheroids and organoids, micro-fluidic Chip platforms and living tissues/animals). These efforts have led to the discovery that Wnt drives metabolic and self-renewal signatures of normal stem cells and cancer stem cells and in turn, intriguing patterns of heterogeneity in tumors and tissue. Our work currently relies on a pipeline of genomics → cell culture → organoid → animal model information.