ADAM19 Promotes EMT ‐Related Changes and Serves as a Prognostic Marker in Circulating Tumor Cells of Renal Cell Carcinoma

Detection of circulating tumor cells (CTCs), particularly characterization of their epithelial-mesenchymal transition (EMT) phenotypes, may improve prognostic accuracy for malignancies. Identification of novel biomarkers for CTC classification may improve the characterization of tumor progression and provide potential therapeutic insights for renal cell carcinoma (RCC). Herein, we identified that a disintegrin and metalloproteinase domain-containing protein 19 (ADAM19) was associated with EMT phenotypes of CTCs. In vitro functional experiments, Western blotting, and RNA sequencing demonstrated that ADAM19 promoted RCC malignant progression and EMT-related changes and was associated with NOTCH and NF-κB signaling pathways. Our findings further suggested potential bidirectional association between ADAM19 and these signaling pathways. CTCs isolated from xenograft mouse models exhibited enhanced proliferative, migratory, and invasive abilities, accompanied by increased ADAM19 expression compared with parental tumor cells. Clinical CTC analysis further revealed that ADAM19-Low-CTCs were associated with unfavorable clinical outcomes in RCC patients. Notably, higher time-updated ADAM19-Low-CTC counts were identified as an independent risk factor for progression-free survival (HR = 1.243, 95% CI: 1.006-1.536).