Targeting cancers where they spawn

Like mini-organisms, tumours aren’t composed of a singular cell type, but instead contain multitudes of subsets behaving in dynamic ways. One population called cancer stem cells (CSCs), for example, can regenerate on their own, effectively acting like a self-sustaining spawn site for malignant cells. While CSCs are known to promote tumour growth and recurrence in brain and colon cancers, their role in gastric tumours has remained elusive. Biomarkers to distinguish these CSCs from the healthy stomach, or even from other cell types within the tumour, lack validation and specificity. “The field has been muddled with potential CSC markers, but none have been shown to consistently identify gastric CSCs in the clinical setting,” said Nick Barker, Deputy Executive Director at the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB). The turning point came when Barker and colleagues discovered high levels of a surface protein, aquaporin-5 (AQP5), in healthy gastric stem cells. This prompted the researchers to look into the cancer context, through a collaborative effort involving the A*STAR Singapore Immunology Network (A*STAR SIgN); A*STAR Infectious Diseases Labs (A*STAR IDL); Nanyang Technological University, Singapore; National University of Singapore; and Kanazawa University in Japan. They used organoid cultures, mouse models and patient biopsies to study AQP5, with molecular profiling revealing the marker’s enriched expression in a subset of cells that also showed gene activity related to stem cell functions. Using antibodies targeting AQP5, the team isolated AQP5-expressing cells from these samples and validated their CSC potential through a range of functional assays. These cells alone, but not their AQP5-negative counterparts, were enough to drive the reestablishment of gastric tumours when transplanted back into the stomach of healthy mice. AQP5 expression also influenced key signalling pathways linked to tumour progression across experimental models. “We found AQP5 to be a highly specific marker to identify gastric CSCs from patient tumours, while itself playing a critical role in promoting rapid cell proliferation, migration and invasion,” Barker explained. “This duality means that strategies against AQP5 could have a therapeutic function against both of these traits, increasing the likelihood of success.” When the team selectively removed AQP5-expressing cells, cancer growth was significantly reduced in mouse models. Repetitive rounds of targeting then eliminated the tumour completely without any signs of long-term recurrence. “The effectiveness of this approach surprised us, suggesting that removing a minor CSC pool within the tumour was sufficient to deliver a significant therapeutic impact,” said Barker. Their study has also supported a patent application on the role of AQP5 in cancer detection and therapeutics. Beyond AQP5 expression, the researchers’ next focus is to better characterise gastric CSCs across broader cancer contexts, including mapping how external signals may prompt their regeneration. Such extensive profiling can help uncover effective, long-term strategies against stomach cancers, Barker said. The A*STAR-affiliated researchers contributing to this research are from the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB), A*STAR Infectious Diseases Labs (A*STAR IDL) and A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB).