LRP6 promotes colitis-associated colorectal cancer via coordinating Wnt/STAT3 signaling and is a pharmaceutical target

LRP6 is a critical co-receptor in the Wnt/β-catenin signaling pathway, but its role, molecular mechanisms, and therapeutic potential in colitis-associated colorectal cancer (CAC) remain elusive. In this study, we identified STAT3 and ALK as novel LRP6-interacting partners using BioID-mass spectrometry, validated via sequential co-immunoprecipitation and cellular co-localization assays. LRP6 promotes ALK-mediated STAT3 Y705 phosphorylation and amplifies STAT3 transcriptional activity. In the AOM/DSS-induced CAC mice, DSS upregulated LRP6 post-transcriptionally, activating Wnt/β-catenin and STAT3 signaling, exacerbating inflammation, and impairing intestinal barrier function. DSS also induced the accumulation of LRP6 and enhanced the Wnt/β-catenin and STAT3 pathways in intestinal epithelial cells. Importantly, conditional knockout of intestinal LRP6 markedly suppressed AOM/DSS-induced CAC progression, alleviating tumor growth and aberrant pathway activation. Consistently, colonic organoids derived from LRP6-deficient crypts exhibited impaired formation capacity, associated with diminished Wnt/β-catenin and STAT3 activity. A SuperTOPFlash screen identified 6-thioguanine (6-TG) as an agent capable of suppressing LRP6 function. 6-TG binds LRP6-ICD and induces lysosomal degradation. Exposure to 6-TG inhibited LRP6-mediated signaling in intestinal epithelial/CRC cells and suppressed AOM/DSS-induced tumorigenesis. Collectively, our findings uncover LRP6’s critical role in CAC by coordinating Wnt/β-catenin and STAT3 pathways, and identify 6-TG as a promising therapeutic agent that partially targets LRP6 for CAC intervention.