Surface Protein AQP5 Is a Functional Marker of Gastric Cancer Stem Cells

Cancer stem cells (CSC) comprise a multipotent population of cancer cells that can self-renew and give rise to progressive disease, underscoring the interest in identifying these populations for cancer research and in targeting these populations for long-term tumor control. However, the biology of CSCs in gastric cancer remains incompletely understood. To this end, Lim, Yada, and colleagues aimed to rigorously identify and functionally establish the role of tumor-resident CSCs within the gastric cancer niche. In genetic mouse models of gastric cancer and patient pyloric tumor samples, the plasma membrane–localized water channel protein, aquaporin 5 (AQP5), labeled a tissue-resident stem cell compartment that was present in the epithelium prior to malignancy and highly expanded in pyloric tumors. AQP5+ epithelial tumor cells were transcriptionally enriched for stem cell programs and displayed signatures associated with extracellular matrix remodeling, epithelial–mesenchymal transition, and drug resistance, distinguishing AQP5 from other previously proposed gastric CSC markers with broader expression or nonfunctional roles. Functional assays demonstrated that AQP5+ cells robustly initiated long-lived organoid cultures and regenerated invasive, heterogeneous tumors in vivo following orthotopic transplantation, whereas AQP5− cells largely lacked sustained self-renewal capacity. Lineage tracing experiments in human tumor organoids further confirmed that AQP5+ cells gave rise to both stem-like and differentiated tumor lineages. Beyond its role as a CSC marker, AQP5 functionally promoted gastric cancer progression, as chemogenetic ablation of AQP5+ cells blocked tumor initiation and induced regression of established tumors in orthotopic mouse tumor models, with consistent results observed in human gastric cancer organoids as AQP5+ cell ablation hindered tumor organoid growth. Mechanistic studies provided evidence that AQP5 enhanced cancer cell proliferation, invasion, and metastatic behavior through the activation of WNT, PI3K, and MAPK signaling across multiple mouse and human experimental models. Together, these findings establish AQP5 not only as a marker but also as a functional driver of gastric CSC activity, with direct implications for therapeutic targeting of stem cell populations in gastric cancer.Lim HYG, Yada S, Murakami K, Lee BTK, Sagiraju S, Phuah P, et al. AQP5: A functional gastric cancer stem cell marker in mouse and human tumors. Science 2025;390:eadr2428.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.