Cancer-associated fibroblasts enhance colorectal cancer lymphatic metastasis via CLEC11A/LGR5-mediated WNT pathway activation
Chuhan Zhang, Teng Pan, Yuyuan Zhang, Yushuai Wu, Anning Zuo, Shutong Liu, Yuhao Ba, Benyu Liu, Shuaixi Yang, Yukang Chen, Hui Xu, Peng Luo, Quan Cheng, Siyuan Weng, Long Liu, Xing Zhou, Jingyuan Ning, Xinwei Han, Jinhai Deng, Zaoqu Liu
Chuhan Zhang, Teng Pan, Yuyuan Zhang, Yushuai Wu, Anning Zuo, Shutong Liu, Yuhao Ba, Benyu Liu, Shuaixi Yang, Yukang Chen, Hui Xu, Peng Luo, Quan Cheng, Siyuan Weng, Long Liu, Xing Zhou, Jingyuan Ning, Xinwei Han, Jinhai Deng, Zaoqu Liu
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Research Article Gastroenterology Oncology

Cancer-associated fibroblasts enhance colorectal cancer lymphatic metastasis via CLEC11A/LGR5-mediated WNT pathway activation

Abstract

Hypoxia in the tumor microenvironment promotes lymphatic metastasis, yet the role of cancer-associated fibroblasts (CAFs) in this process remains insufficiently elucidated in colorectal cancer (CRC). In this study, we developed a large language model–based cellular hypoxia–predicting classifier to identify hypoxic CAFs (HCAFs) at single-cell resolution. Our findings revealed that HCAFs enhance CRC lymphatic metastasis by secreting CLEC11A, a protein that binds to the LGR5 receptor on tumor cells, subsequently activating the WNT/β-catenin signaling pathway. This promotes epithelial-mesenchymal transition and lymphangiogenesis, facilitating the spread of tumor cells via the lymphatic system. Furthermore, we demonstrate that the hypoxia-induced transcription factor HIF1A regulates the conversion of normoxic CAFs to HCAFs, driving CLEC11A expression and promoting metastasis. In vivo and vitro experiments confirmed the pro-metastatic role of CLEC11A in CRC, with its inhibition reducing lymphatic metastasis. This effect was markedly reversed by targeting the LGR5 receptor on tumor cells or inhibiting the WNT/β-catenin pathway, further elucidating the underlying mechanisms of CLEC11A-driven metastasis. These findings underscore the potential of targeting the CLEC11A-LGR5 axis to prevent lymphatic dissemination in CRC. Our study highlights the role of HCAFs in CRC progression and reveals mechanisms of lymphatic metastasis for intervention.

Authors

Chuhan Zhang, Teng Pan, Yuyuan Zhang, Yushuai Wu, Anning Zuo, Shutong Liu, Yuhao Ba, Benyu Liu, Shuaixi Yang, Yukang Chen, Hui Xu, Peng Luo, Quan Cheng, Siyuan Weng, Long Liu, Xing Zhou, Jingyuan Ning, Xinwei Han, Jinhai Deng, Zaoqu Liu

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Figure 8

CLEC11A promotes lymphangiogenesis and lymphatic metastasis through its interaction with LGR5 on tumor cells.

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CLEC11A promotes lymphangiogenesis and lymphatic metastasis through its ...
(A) Identification of ligand-receptor pairs and a schematic of the TimeCCI pipeline, illustrating the calculation of Spearman’s correlation coefficients (SCC) for covarying ligand-receptor pairs between HCAFs and tumor cells. (B) CLEC11A-LGR5 is the top ligand-receptor pair, with the highest SCC among CLEC11A interactions. (C) Normalized interaction probabilities between CLEC11A and its receptors across different cell types. (D) ST data showing CLEC11A-LGR5 interactions. (E) Molecular dynamics simulation of the CLEC11A-LGR5 complex, with structural visualization of key interacting residues. (F) mIHC revealing spatial colocalization between CLEC11A and LGR5. Scale bar: 50 μm. (G) Co-IP confirmed the physical interaction between CLEC11A and LGR5 in SW480 cells.