MTAP deficiency enhances collective metastasis in non-small cell lung cancer via WNT3A methylation.

Collective cell migration (CCM) is a pivotal driver of tumor progression and metastasis in non-small cell lung cancer (NSCLC), yet its upstream regulatory mechanisms remain poorly understood. Here, we investigated the functional role and molecular mechanism of MTAP deficiency in modulating CCM in NSCLC. Clinical sample analysis revealed that NSCLC patients with MTAP deficiency exhibited significantly shorter overall survival. Using a three‑dimensional culture system, we verified that MTAP deficiency had little effect on cell proliferation, but markedly promoted CCM by inducing cytoskeletal rearrangement of leader cells within tumor clusters. Mechanistically, MTAP deletion leads to intracellular MTA accumulation, which suppresses PRMT5 activity and reduces global protein symmetric dimethylarginine (sDMA) modification. Decreased sDMA further enhances USF2 phosphorylation and nuclear translocation, facilitates USF2 binding to the WNT3A promoter, and concurrently reduces DNA CpG methylation of the WNT3A promoter, thereby synergistically activating WNT3A transcription. Upregulated WNT3A strengthens intercellular crosstalk between leader and follower cells, elevates adhesion among follower cells, and drives cytoskeletal remodeling in leader cells, ultimately accelerating CCM progression. Pharmacologically, the WNT3A specific inhibitor C59 effectively blocked CCM formation and mitigated collective metastasis in MTAP‑deficient NSCLC. In summary, our results define a novel MTAP-PRMT5-sDMA-WNT3A regulatory axis that controls CCM and malignant progression of NSCLC. Targeting WNT3A represents a promising therapeutic strategy for the clinical treatment of MTAP‑deficient NSCLC.