Cancer-associated fibroblasts-derived CAV1 promotes epithelial-mesenchymal transition and stemness in bladder cancer through activation of the LIF/STAT3 signaling pathway.
BACKGROUND Cancer-associated fibroblasts (CAFs) are key components of the bladder cancer microenvironment, but how specific CAF subpopulations drive malignant progression remains unclear. This study aimed to identify CAF driver genes and elucidate the role of caveolin-1 (CAV1) in CAF-mediated bladder cancer progression. METHODS Single-cell RNA sequencing and public bladder cancer datasets were integrated to identify fibroblast-associated candidate genes and evaluate the clinical significance of CAV1. Clinical samples were analyzed by immunofluorescence. The biological functions of CAV1 were further evaluated through CAF-bladder cancer cell co-culture systems, gain- and loss-of-function experiments, and comprehensive molecular analyses. The downstream mechanism was explored through LIF stimulation, STAT3 silencing, and validated in a subcutaneous xenograft model. RESULTS Single-cell analysis identified CAV1 as a fibroblast-associated gene linked to stemness- and ferroptosis-related signatures. High CAV1 expression predicted poor prognosis and was independently associated with unfavorable survival. CAV1 expression positively correlated with fibroblast infiltration and was enriched in a subset of ACTA2-positive CAFs. CAFs markedly promoted multiple malignant behaviors of bladder cancer cells, whereas silencing CAV1 effectively counteracted these pro-tumorigenic effects. Mechanistically, CAV1 enhanced LIF expression in CAFs, thereby activating JAK2/STAT3 signaling in tumor cells. Pharmacological inhibition of STAT3 abolished the tumor-promoting effects of CAFs both in vitro and in vivo. CONCLUSIONS CAF-derived CAV1 promotes bladder cancer progression by activating the LIF-STAT3 signaling axis. Targeting stromal CAV1-mediated STAT3 signaling may represent a promising therapeutic strategy for bladder cancer.