Wnt5a suppresses colorectal cancer progression via TGF-β/NOTUM/OLFM4 axis in patient-derived organoids.

IF 8.2 2区生物学 Q1 CELL BIOLOGY

Cell Communication and Signaling Pub Date : 2025-08-05 DOI:10.1186/s12964-025-02364-z

Yewei Huang, Jiahao Huang, Jiazi Yu, Songlin Zhuang, Ming Liu

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引用次数: 0

Abstract

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.

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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。

背景：Wnt5a是一种非规范的Wnt配体，在癌症进展中表现出双重作用，但其在结直肠癌（CRC）中的肿瘤抑制机制仍不明确。肿瘤微环境中的基质来源信号（TME）越来越被认为是CRC行为的关键调节剂，但它们与治疗耐药性的相互作用尚不清楚。方法：使用患者来源的CRC类器官（PDOs）和功能分析，我们研究了基质分泌的Wnt5a的作用。机制研究结合RNA测序、药物抑制和免疫荧光解剖Wnt5a/TGF-β/NOTUM/OLFM4轴。药物敏感性试验评估Wnt5a与5-氟尿嘧啶（5-FU）的协同作用。结果：Wnt5a主要来源于基质，通过激活TGF-β/Smad2信号，上调Wnt抑制剂NOTUM，下调干性标志物OLFM4，抑制CRC类器官生长。RNA-seq显示NOTUM诱导是关键的介质。Wnt5a与5-FU联合可协同增强类器官生长抑制和细胞死亡，逆转5-FU驱动的NOTUM下调。结论：我们的研究确定了一种新的基质- tme串扰机制，其中Wnt5a通过TGF-β/NOTUM/OLFM4信号抑制CRC进展。Wnt5a和5-FU的联合疗效突出了克服化疗耐药的有希望的策略。这些发现强调了靶向基质来源通路在结直肠癌中的治疗潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

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.