Yewei Huang, Jiahao Huang, Jiazi Yu, Songlin Zhuang, Ming Liu
{"title":"Wnt5a通过TGF-β/NOTUM/OLFM4轴在患者来源的类器官中抑制结直肠癌的进展。","authors":"Yewei Huang, Jiahao Huang, Jiazi Yu, Songlin Zhuang, Ming Liu","doi":"10.1186/s12964-025-02364-z","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Wnt5a, 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.</p><p><strong>Methods: </strong>Using 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).</p><p><strong>Results: </strong>Wnt5a 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.</p><p><strong>Conclusions: </strong>Our 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.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"365"},"PeriodicalIF":8.2000,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323272/pdf/","citationCount":"0","resultStr":"{\"title\":\"Wnt5a suppresses colorectal cancer progression via TGF-β/NOTUM/OLFM4 axis in patient-derived organoids.\",\"authors\":\"Yewei Huang, Jiahao Huang, Jiazi Yu, Songlin Zhuang, Ming Liu\",\"doi\":\"10.1186/s12964-025-02364-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Wnt5a, 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.</p><p><strong>Methods: </strong>Using 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).</p><p><strong>Results: </strong>Wnt5a 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.</p><p><strong>Conclusions: </strong>Our 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.</p>\",\"PeriodicalId\":55268,\"journal\":{\"name\":\"Cell Communication and Signaling\",\"volume\":\"23 1\",\"pages\":\"365\"},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2025-08-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323272/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Communication and Signaling\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1186/s12964-025-02364-z\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Communication and Signaling","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s12964-025-02364-z","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Wnt5a suppresses colorectal cancer progression via TGF-β/NOTUM/OLFM4 axis in patient-derived organoids.
Background: Wnt5a, 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.
Methods: Using 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).
Results: Wnt5a 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.
Conclusions: Our 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.
期刊介绍：
Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior.
Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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