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

  • Cell Commun Signal. 2025 Aug 5;23(1):365. doi: 10.1186/s12964-025-02364-z.
Yewei Huang  1  2 ,  Jiahao Huang  1 ,  Jiazi Yu  3 ,  Songlin Zhuang  4 ,  Ming Liu  5  6
Affiliations
  • 1. Yongjiang Laboratory (Y-LAB), Ningbo, Zhejiang, 315202, China.
  • 2. Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
  • 3. Department of General Surgery, Ningbo Medical Treatment Centre Li Huili Hospital, Ningbo, 315040, China.
  • 4. Yongjiang Laboratory (Y-LAB), Ningbo, Zhejiang, 315202, China. [email protected].
  • 5. Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. [email protected].
  • 6. Heilongjiang Province Key Laboratory of Digestive Surgery and Nutrition & Metabolism, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. [email protected].
PMID: 40765051 DOI: 10.1186/s12964-025-02364-z
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.

Keywords
Chemosensitization; Colorectal cancer progression; NOTUM; Wnt5a.
Products