Exosomal CCT6A Secreted by Cancer‐Associated Fibroblasts Interacts with β‐Catenin to Enhance Chemoresistance and Tumorigenesis in Gastric Cancer

作者：Hui Sun, Tianqi Zhang, Xiaoyan Zhang, Yingxue Liu, Xu Wang, Xin Wang, Cong Tan, Shujuan Ni, Weiwei Weng, Meng Zhang, Lei Wang, Dan Huang, Xiaoyu Wang, Wenfeng Wang, Weiqi Sheng, Mi‐die Xu · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202506674 · 被引用次数：10 · 研究领域：Galectins and Cancer Biology、Extracellular vesicles in disease、Protease and Inhibitor Mechanisms

Cancer-associated fibroblasts (CAFs) are pivotal components of the tumor microenvironment that drive gastric cancer (GC) progression and chemoresistance. Here, CCT6A is identified as a CAF-derived factor whose high expression is positively associated with GC progression and plays a key regulatory role in stemness, chemoresistance, and glucose metabolism. In a co-culture system of CAFs and cancer cells, it is discovered that CCT6A is transferred from CAFs to tumor cells mainly via exosomal transport, thereby enhancing stemness, chemoresistance, and glycolysis. Mechanistically, CCT6A interacts with β-catenin, inducing its phosphorylation and nuclear translocation, which subsequently leads to transcriptional suppression of the glycolysis inhibitors DDIT4 and TXNIP through c-Myc activation. Furthermore, a feedforward regulatory loop is uncovered in which the CCT6A pseudogene CCT6P1 acts as a competitive endogenous RNA (ceRNA) by sequestering miR-922, thereby stabilizing CCT6A expression, while c-Myc co-activates both CCT6A and CCT6P1, amplifying oncogenic signaling. Collectively, the findings not only reveal the pivotal mediator of CAF-secreted CCT6A in orchestrating stemness, chemoresistance, and metabolic reprogramming in GC but also highlight its dual utility as a diagnostic biomarker and therapeutic target.