ArticleCell communication and signaling : CCS2025
Wnt5a suppresses colorectal cancer progression via TGF-β/NOTUM/OLFM4 axis in patient-derived organoids.
Article in Cell communication and signaling : CCS, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- Review
- Characterization of the tumor microenvironment in locally advanced gastric cancer and identification of spatially predictive biomarkers associated with beneficial neoadjuvant immunochemotherapy.Frontiers in immunology · 2026Article
- Patient-derived organoids (PDOs) as a promising platform for personalized treatment of colorectal cancer: current applications and future challenges.Cancer biology & therapy · 2025Review
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5 authors.
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Abstract
backgroundWnt5a, a noncanonical Wnt ligand, exhibits dual roles in cancer progression, but its tumor-suppressive mechanisms in colorectal cancer (CRC) remain poorly defined. Stromal-derived signals in the tumor microenvironment (TME) are increasingly recognized as critical modulators of CRC behavior, yet their interplay with therapeutic resistance is unclear.
methodsUsing patient-derived CRC organoids (PDOs) and functional assays, we investigated the role of stromal-secreted Wnt5a. Mechanistic studies combined RNA sequencing, pharmacological inhibition, and immunofluorescence to dissect the Wnt5a/TGF-β/NOTUM/OLFM4 axis. Drug sensitivity assays evaluated the synergy between Wnt5a and 5-fluorouracil (5-FU).
resultsWnt5a was predominantly stromal-derived and suppressed CRC organoid growth by activating TGF-β/Smad2 signaling, which upregulated the Wnt inhibitor NOTUM and downregulated the stemness marker OLFM4. RNA-seq revealed NOTUM induction as the key mediator. Combining Wnt5a with 5-FU synergistically enhanced organoid growth inhibition and cell death, reversing 5-FU-driven NOTUM downregulation.
conclusionsOur study identifies a novel stromal-TME crosstalk mechanism wherein Wnt5a restrains CRC progression via TGF-β/NOTUM/OLFM4 signaling. The combinatorial efficacy of Wnt5a and 5-FU highlights a promising strategy to overcome chemoresistance. These findings emphasize the therapeutic potential of targeting stromal-derived pathways in CRC.
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