Versatile roles of annexin A4 in clear cell renal cell carcinoma: Impact on membrane repair, transcriptional signatures, and composition of the tumor microenvironment

Clear cell renal cell carcinoma (ccRCC) is the most prevalent renal malignancy with a poor prognosis when metastasized. The invasive growth of cancer cells relates to membrane-damaging forces, but the relevance of plasma membrane repair machinery in ccRCC remains incompletely understood. Employing proteomics, analysis of scRNA-sequencing data, and multiplex imaging, we identified ANXA4 as selectively expressed in ccRCC, with distinct localization patterns at the plasma and nuclear membranes. Genetic titration studies demonstrated that reduced ANXA4 expression impairs membrane repair and invasive capabilities. Further segmentation analysis of ANXA4-low tumors showed a distinct composition of the tumor microenvironment, with increased tumor-infiltrating lymphocytes and acellular extracellular matrix deposition. Transcriptomic analysis demonstrated alterations in epithelial-mesenchymal transition and immune signaling signatures in ANXA4-low tumors. Transcription factor enrichment analysis identified ELF3 as a regulator of invasive properties. Our integrative approach uncovered multiple roles for ANXA4 in modulating membrane repair, transcriptional regulation, and shaping the ccRCC tumor microenvironment composition.