Caveolin-1 mediates the utilization of extracellular proteins for survival in refractory gastric cancer

Abstract Despite advances in cancer therapy, the clinical outcome of patients with gastric cancer remains poor largely due to tumor heterogeneity. Thus, finding a hidden vulnerability of clinically refractory subtypes of gastric cancer is crucial. Here, we report that chemo-resistant gastric cancer cells heavily rely on endocytosis, facilitated by caveolin-1, for survival. caveolin-1 was highly up-regulated in the most malignant SEM (stem-like, EMT, and mesenchymal)-type gastric cancer cells, allowing caveolin-1-mediated endocytosis and utilization of extracellular proteins via lysosomal degradation. Down-regulation of caveolin-1 alone was sufficient to induce cell death in SEM-type gastric cancer cells, emphasizing its importance as a survival mechanism. Consistently, chloroquine, the lysosomal inhibitor, successfully blocked caveolin-1-mediated endocytosis, leading to the marked suppression of tumor growth in chemo-refractory gastric cancer cells in vitro including patient-derived organoids, and in vivo. Together, our findings suggest that caveolin-1-mediated endocytosis is a key metabolic pathway for gastric cancer survival and a potential therapeutic target.