Wnt5b, a member of the WNT family closely related to Wnt5a, is crucial for cell migration, proliferation, and differentiation in many cell types. It signals through the non-canonical β-catenin-independent pathway and often acts as an antagonist of canonical WNT signaling. Wnt5b is involved in various developmental pathways, both in normal and pathological physiology [1,2].

In osteosarcoma, Wnt5b is the most abundant WNT expressed in tumors. Its expression correlates with metastasis, histologic subtype, and reduced survival. Wnt5b is enriched in osteosarcoma stem cells, inducing the expression of the stemness gene SOX2, promoting sphere-related properties, cell proliferation, migration, and chemoresistance to methotrexate. In vivo, it increases lung and liver metastasis and inhibits hyaluronic acid via upregulation of hyaluronidase 1 (HYAL1). Targeting Wnt5b through inhibition of WNT/ROR1 signalling with an antibody to ROR1 reduces stemness properties [3].

In non-small cell lung cancer (NSCLC), Wnt5b overexpression in specimens correlates with advanced TNM stage, lymph node metastasis, and poor prognosis. Wnt5b promotes the malignant phenotype of NSCLC cells via the FZD3-DVL3-RAC1-PCP-JNK pathway [4].

In Pacific white shrimp, Wnt5b expression is regulated by the IMD-Relish and JAK-STAT pathways and suppressed upon bacterial infection. Silencing Wnt5b in vivo increases the expression of several antimicrobial peptides, while treatment with recombinant Wnt5b protein increases the susceptibility to Vibrio parahaemolyticus infection, suggesting it plays a negative role in antibacterial response [5].

In colorectal cancer, oncogenic KRAS activates the transcription factor CP2 which upregulates Wnt5b, triggering the transformation of carcinoma-associated fibroblasts into lipid-rich CAFs that produce VEGFA to spur angiogenesis [6].

In bone cancer pain, the protein expression of Wnt5b and its receptor Ryk is upregulated in ipsilateral DRGs in tumor-bearing mice. Wnt5b/Ryk promotes the trafficking of P2X3 receptors to the membrane via the activation of CaMKII in primary sensory neurons, resulting in peripheral sensitization and bone cancer-induced pain [7].

In conclusion, Wnt5b is essential for multiple biological processes, and its dysregulation is associated with various diseases such as osteosarcoma, NSCLC, antibacterial response in shrimp, colorectal cancer, and bone cancer pain. Studies using different models have revealed its diverse roles in these disease conditions, providing potential therapeutic targets for treatment.