Experimental and Molecular Medicine · Published 2026-06-03 · DOI 10.1038/s12276-026-01735-x
Zhengnan Huang, Yilin Yan, Xinan Wang, Huaxing Li, Jingming Zhuang, Xiangqian Cao, Yang Wang, Denglong Wu, Bing Shen
Abstract The mechanisms underlying lung metastases in bladder cancer (BLCA) remain poorly understood. Cancer-associated fibroblasts (CAFs) are key modulators of the metastatic microenvironment, but how they are activated and contribute to BLCA lung metastases remains unclear. Single-nucleus RNA sequencing was conducted on metastatic lung lesions from patients with BLCA to characterize the tumor microenvironment. Functional and molecular biology experiments, including co-culture assays, luciferase reporter assays, chromatin immunoprecipitation and in vivo lung metastasis models, were performed to explore the mechanisms by which tumor-derived factors and CAFs-secreted exosomes contribute to metastasis. The results revealed that CAFs were enriched in metastatic lung lesions and activated by tumor-derived WNT7A via the Wnt/β-catenin pathway. These activated CAFs promoted BLCA cell proliferation, stemness and migration through the exosomal delivery of miR-1910-5p, which directly suppressed CTDNEP1 expression and activated MYC signaling. Mechanistically, RBMX was identified as a regulator of miR-1910-5p packaging into CAFs-derived exosomes. In vivo, inhibition of CAFs-derived exosomes secretion reduced lung metastasis, highlighting their critical role in metastasis formation. In conclusion, this study uncovers a novel reciprocal activation loop between tumor cells and CAFs in BLCA lung metastases, where tumor-secreted WNT7A activates resident pulmonary CAFs, which in turn enhance tumor malignancy through exosomal delivery of miR-1910-5p. This exosome-mediated crosstalk promotes metastatic progression via the CTDNEP1/MYC signaling pathway. These findings provide potential therapeutic targets for mitigating metastatic progression in BLCA.
Abstract from DOAJ. Public domain (CC0 1.0).
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Huang, Z., Yan, Y., Wang, X., et al. (2026). Tumor-derived WNT7A reprograms pulmonary fibroblasts to remodel the metastatic niche and promote bladder cancer lung metastasis. Experimental and Molecular Medicine. https://doi.org/10.1038/s12276-026-01735-x