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 7

ELN/TGFBR2 axis accelerates BCa lymph node metastasis.

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ELN/TGFBR2 axis accelerates BCa lymph node metastasis. (A) Schematic of ...
(A) Schematic of the footpad metastasis model illustrating the primary footpad tumor and draining popliteal LNs. (B and C) Bioluminescence imaging (B) and quantification of luminescence intensity (C) in popliteal LNs from mice treated with IgG, rm-ELN + IgG, rm-ELN + ITD1, or rm-ELN + αTGF-β. n = 7–8 for each group. P values were determined by 1-way ANOVA followed by Tukey’s multiple-comparison test. (D and E) Representative images of isolated popliteal LNs (D) and quantification of metastatic LN volumes (E) across treatment groups. P values were determined by 1-way ANOVA followed by Tukey’s multiple-comparison test. (F and G) H&E staining and anti-luciferase IHC (F) of metastatic LNs, with quantification of positive IHC area percentage (G). P values were determined by 1-way ANOVA followed by Tukey’s multiple-comparison test. (H and I) Representative immunofluorescence images (H) of TGF-β1 (red, top) and TGFBR2 (red, bottom) in PanCK+ (green) metastatic lymph nodes, with corresponding quantification of MFI (I). Scale bar: 100 μm. P values were determined by 1-way ANOVA followed by Tukey’s multiple-comparison test. Data are shown as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.