: The study of stem cell regulation in intestinal and colonic tissues is an area of significant focus within the scientific community, providing mechanistic insight into biological process and offering translational clinical potential. In this thesis we address the contribution of NOTCH signaling in maintaining the stem cell niche by modulating the mode of stem cell division and receptor-ligand interactions for cell-cell communication. Furthermore, we examine NOTCHmediated spatiotemporal recovery of the intestinal stem cell (ISC) niche following single cell ablation. Finally, we demonstrate that elevated NOTCH signaling exists under conditions of physiological stress and in colon cancer initiating cells (CCICs), promoting tumorigenic potential of the intestinal epithelium. Overall, our research highlights the underlying complexities of NOTCH signaling as an essential pathway to maintain intestinal homeostasis and may inspire development of novel CRC therapeutic strategies. Research efforts and findings during my graduate study have been consolidated into the following peer-reviewed publications, of which the four first co-author manuscripts are described in detail in this dissertation. 1. Srinivasan, Tara; Walters, Jewell; Bu, Pengcheng; Than, Elaine B.; Tung, Kuei-Ling; Chen, Kai-Yuan; Panarelli, Nicole; Milsom, Jeff; Augenlicht, Leonard; Lipkin, Steven M; Shen, Xiling. "NOTCH Signaling Regulates Asymmetric Division of Fast- and Slow-Cycling Colon Cancer Initiating Cells." Cancer Research, 2016. (in press) 2. Srinivasan, Tara; Than, Elaine B.; Bu, Pengcheng; Tung, Kuei-Ling; Chen, Kai-Yuan; Augenlicht, Leonard; Lipkin, Steven M.; Shen, Xiling. "NOTCH Signaling Regulates Fast- and Slow-Cycling Intestinal Stem Cells." Scientific Reports, 2016. (in press) 3. Chen, Kai-Yuan*; Srinivasan, Tara*; Choi, Jiahn*; Bu, Pengcheng; Tung, Kuei-Ling; Nishimura, Nozomi; Shen, Xiling. "Dynamic regulation of intestinal stem cell niche recovery in real-time." Cell Systems, 2015. (in review) 4. Murthy, Preetish KL*; Srinivasan, Tara*; Bochter, Skye; Bu, Pengcheng; Cole, Susan; Shen, Xiling. "FRINGE-dependent modification of NOTCH Ligands in Intestinal Stem Cells." 2016. (in preparation) 5. Rothschild, Daniel; Srinivasan, Tara; Aponte-Santiago, Linette; Shen, Xiling; Irving, Allen. "The Ex Vivo Culture and Pattern Recognition Receptor Stimulation of Mouse Intestinal Organoids." JoVE, 2015. (in press) 6. Bu, Pengcheng*; Wang, Lihua*; Chen, Kai-Yuan; Srinivasan, Tara; Lakshminarasimha, Preetish; Tung, Kuei-Ling; Varanko, Anastasia; Ai, Yiwei; Lipkin, Steven; Shen, Xiling. "miR34a and Numb synergize for asymmetric cell fate determination." Cell Stem Cell, 2016 Feb 4;18(2):189-202. 7. Crespo, Miguel; Tsai, Su-Yi; Srinivasan, Tara; Pipalia, Nina; Maxfield, Nina; Lipkin, Steven M; Evans, Todd; Chen, Shuibing. "Colonic Organoids Derived from Human Pluripotent Stem Cells for Modeling Colorectal Cancer and Drug Testing." Nature Medicine, 2015. (in review) 8. Wang, Lihua*; Bu, Pengcheng*; Ai, Yiwel; Srinivasan, Tara; Lipkin, Steven M; Shen, Xiling. "A Long Non-Coding RNA Targets MicroRNA miR-34a to Regulate Colon Cancer Stem Cell Asymmetric Division." eLife, 2016. (in press)