Tumor-derived WNT7A reprograms pulmonary fibroblasts to remodel the metastatic niche and promote bladder cancer lung metastasis

www.nature.com/emm ARTICLE OPEN Tumor-derived WNT7A reprograms pulmonary fibroblasts to remodel the metastatic niche and promote bladder cancer lung metastasis Zhengnan Huang1,2,7, Yilin Yan3,7, Xinan Wang1,7, Huaxing Li4, Jingming Zhuang4, Xiangqian Cao3, Yang Wang3, Denglong Wu1 ✉ Bing Shen1,3,4,5,6 ✉ and 1234567890();,: © The Author(s) 2026 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 tumorderived 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 CAFsderived 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. Experimental & Molecular Medicine; https://doi.org/10.1038/s12276-026-01735-x INTRODUCTION Lung metastasis is the most common event of distant metastases in bladder cancer (BLCA) and a leading cause of BLCA-related mortality1,2. Tumor metastasis is a complex, multi-stage process, with the colonization and subsequent proliferation in distant organs to form micrometastases being the most intricate and ratelimiting step3. Cancer stem-like cells from the primary tumor site, upon invading distant organs, can exploit and remodel the surrounding microenvironment. This remodeling enables the microenvironment to provide signals that sustain their proliferation and stemness, thus facilitating the colonization of cancer stem-like cells in distant organs4. Once remodeled to support tumor cell colonization, this microenvironment is referred to as the metastatic niche. The formation of the metastatic niche is a complex process involving multiple cellular interactions, in which fibroblasts, as a core component of this microenvironment, play a crucial role in its establishment. Normal fibroblasts (NFs), when stimulated by the tumor microenvironment, are activated and transdifferentiated into cancer-associated fibroblasts (CAFs). Activated CAFs regulate extracellular matrix remodeling by secreting various cytokines, chemokines, matrix metalloproteinases and other factors, thereby altering the physical and chemical properties of microenvironment and providing a favorable environment for tumor cell colonization5. The molecular mechanisms by which CAFs promote tumor metastasis have been elucidated. For instance, studies have shown that activated CAFs play a critical role in enabling the colonization of salivary adenoid cystic carcinoma cells in the lung6. Moreover, research has demonstrated that hepatocellular carcinoma cells can induce the activation and conversion of fibroblasts into CAFs, which subsequently secrete chemokines such as IL-6 to facilitate the lung metastasis of liver cancer.7 Exosomes, which are small membranous vesicles with a size range of 30–150 nm, serve as essential cellular communicators, encapsulating a diverse array of proteins, lipids, mRNAs, miRNAs and lncRNAs8–10. Extensive research has demonstrated that exosomes regulate the tumor microenvironment, thereby facilitating cancer metastasis and progression11,12. Among the various 1 Department of Urology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China. 2Department of Urology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. 3Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China. 4Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. 5Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai, China. 6Tongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China. 7These authors contributed equally: Zhengnan Huang, Yilin Yan, Xinan Wang. ✉email: ; Received: 26 May 2025 Revised: 8 January 2026 Accepted: 12 March 2026 Z. Huang et al. 2 molecules carried by exosomes, miRNAs have garnered substantial attention due to their involvement in immunomodulation, chemoresistance and metastasis across multiple tumor types. miRNAs within exosomes can be internalized by adjacent or distant cells, where they promote oncogenic signaling by suppressing target mRNAs in the recipient cells13,14. WNT7A, a member of the Wnt family, is a secreted glycoprotein that serves as a key component of the Wnt signaling pathway, playing pivotal roles in diverse physiological and pathological processes through pathway activation15,16. Our previous study revealed that WNT7A expression was significantly upregulated in BLCA tissues compared with normal bladder epithelium. Furthermore, WNT7A was shown to enhance the invasive capacity of BLCA cells by activating the Wnt signaling pathway. In vivo experiments further revealed that overexpression of WNT7A markedly promotes the lung metastatic potential of BLCA cells17. However, the molecular mechanisms underlying the role of WNT7A in facilitating lung metastasis in BLCA remain to be elucidated. In this study, we aim to elucidate the molecular mechanisms underlying lung metastasis in BLCA. Through comprehensive analyses, we demonstrate that tumor-derived WNT7A plays a critical role in remodeling the metastatic microenvironment by inducing the activation of NFs into CAFs. miRNA microarray profiling identified miR-1910-5p as a key differentially expressed molecule in exosomes derived from NFs and CAFs. Subsequent functional studies revealed that exosomal miR-1910-5p is transferred from CAFs to BLCA cells, promoting malignant phenotypes and facilitating their colonization and metast (...truncated)