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 convers

SUBMITTER: Zhang C 

PROVIDER: S-EPMC12520694 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature