ELN orchestrates prometastatic and immunosuppressive niche in bladder cancer via TGFB1 autocrine signaling
Wentao Xu, Jia Gao, Shanshan Wu, Jianshang Huang, Chenchen An, Chonggui Jiang, Nianping Liu, Chen Cheng, Zihan Wang, Zijian Dong, Yuchen Xu, Jun Zhou, Hanren Dai, Xiaolei Li, Honghai Xu, Songyun Zhao, Qianwen Fan, Yang Li, Ying Dai, Li Zuo, Hua Wang
Wentao Xu, Jia Gao, Shanshan Wu, Jianshang Huang, Chenchen An, Chonggui Jiang, Nianping Liu, Chen Cheng, Zihan Wang, Zijian Dong, Yuchen Xu, Jun Zhou, Hanren Dai, Xiaolei Li, Honghai Xu, Songyun Zhao, Qianwen Fan, Yang Li, Ying Dai, Li Zuo, Hua Wang
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Research Article Immunology Oncology

ELN orchestrates prometastatic and immunosuppressive niche in bladder cancer via TGFB1 autocrine signaling

Abstract

Bladder cancer (BCa) mortality is mainly driven by metastatic dissemination and an immunosuppressive tumor microenvironment. Here, we identify ELN (tropoelastin), an extracellular matrix protein abundantly secreted by cancer-associated fibroblasts (CAFs), as a critical determinant of these processes and a marker of poor prognosis. ELN promotes epithelial-mesenchymal transition (EMT), facilitates lymphatic spread, and induces immune dysfunction characterized by macrophage polarization toward an M2 phenotype and T cell exhaustion. Mechanistically, ELN functions as a binding partner of TGF-β receptor 2 (TGFBR2), thereby triggering SMAD2/3-dependent TGF-β1 secretion and establishing a feed forward signaling loop. This ELN/TGFBR2/TGF-β1 axis amplifies metastatic capacity and immunosuppressive signaling, ultimately accelerating disease progression and diminishing responsiveness to immune checkpoint blockade. Functional studies in BCa organoids and murine models demonstrated that pharmacologic blockade of the ELN-TGFBR2 interaction effectively suppressed tumor metastasis and restored antitumor immunity. Collectively, our findings establish ELN as a CAF-derived driver of metastasis and immune evasion in BCa. Targeting the ELN-TGFBR2 interaction offers a promising therapeutic strategy to limit metastatic progression and enhance the efficacy of immunotherapy in this lethal disease.

Authors

Wentao Xu, Jia Gao, Shanshan Wu, Jianshang Huang, Chenchen An, Chonggui Jiang, Nianping Liu, Chen Cheng, Zihan Wang, Zijian Dong, Yuchen Xu, Jun Zhou, Hanren Dai, Xiaolei Li, Honghai Xu, Songyun Zhao, Qianwen Fan, Yang Li, Ying Dai, Li Zuo, Hua Wang

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Figure 1

ELN expression correlates with BCa progression and poor clinical outcomes.

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ELN expression correlates with BCa progression and poor clinical outcom...
(A) Heatmap shows the Spearman correlation between the expression of 5 candidate genes and signature scores for immunosuppression (top) and EMT (bottom) across multiple BCa high-throughput sequencing datasets. Correlation coefficients and P values were determined using Spearman’s correlation analysis. (B and C) Kaplan-Meier analysis of OS (B) and PFS (C) in TCGA-BLCA cohort (ELN_high = 204, ELN_low = 204). P values were determined by log-rank test. (D) ELN expression in primary tumors stratified by clinicopathological features in the TCGA-BLCA cohort, including tumor grade, clinical stage, molecular subtype, T stage, and N stage. P values were determined by Kruskal-Walli’s test. (E) ELN expression stratified by immunotherapy response and molecular subtype in the IMvigor210 cohort (n = 298). P values were determined by 2-tailed Mann-Whitney U test (left) and Kruskal-Wallis test (right). (F) Representative immunofluorescence staining of ELN (magenta) in metastatic (non-N0) and nonmetastatic (N0) BCa tissues. Nuclei were counterstained with DAPI (gray). Scale Bar: 50 μm. (G) Quantification of mean fluorescence intensity (MFI) of ELN in N0 versus non-N0 tissues. n = 6 for each group. P value was determined by 2-tailed Student’s t test. (H) UMAP visualization of 94,542 single cells from 12 human BCa tissues, annotated by major cell populations. (I) UMAP plot displaying cell origins grouped by status of epithelial cells (normal vs. malignant). (J) Quantitative comparison of EMT signature scores in malignancies between ELN_high and ELN_low groups. P value was determined by 2-tailed Mann-Whitney U test. Data are shown as mean ± SEM. **P < 0.01, ****P < 0.0001.