Isolating endogenous gastric stem cells and their cancer counterparts is challenging due to a lack of useful surface markers. We recently identified Aqp5 as a membrane marker that facilitates enrichment of both human and mouse pyloric stem cells. Using mouse models and organoid assays, we further identify Aqp5-expressing populations in gastric cancers as cancer stem cells (CSC’s), identifying them as a potential therapeutic target. Ongoing investigation of AQP5 roles in conferring key cancer traits using organoid, lineage tracing and orthotopic transplantation models will be discussed. In parallel, we have identified two new markers of colon stem cell populations in distinct regions of the colon. Using novel mouse models, we demonstrate that colon stem cells are key sources of colon cancer in the caecum and distal colon. Potential uses of these new colon stem cell drivers for generating advanced models of regional colon cancer will be discussed. Finally, recent work on potential contributions of Lgr5+ and Lgr6+ cells to ESCC will be introduced.