Intracellular complement proteins are tumor-promoting effectors and poor prognosis biomarkers in renal cancer

Abstract Clear cell renal carcinoma (ccRCC) tumors highly express proteins of the complement system, a major innate immune defense mechanism. Exploring spatial transcriptome and making an atlas staining patterns by ultra-high multiplex imaging ccRCC tumor sections, we revealed presence regions with co-regulated overexpression components, including C3 Factor H (FH). The strong for these correlated poor prognosis in patient cohort. These interacted physically lysosomes cells situ, as evidenced proximity ligation assay. We discovered previously unrecognized intracellular functions FH cells. knockdown resulted formation more compact tumorospheres than control hampered energy metabolism, while perturbed sphere-forming capacity due to decreased viability proliferation enhanced Krebs cycle. For two act together intracellularly, being negative regulator C3. also function independently each other, regulating gene transcription. interactome mass spectrometry, found that transcription factors regulate cycle proteins, controlling actin cytoskeleton remodeling, explaining altered morphology reduced motility FH-deficient In conclusion, are multitasking effectors, impacting multiple hallmarks cancer - enabling replicative immortality, stimulating proliferation, resisting death, deregulating cellular bearing potential new therapeutic targets. main author was supported DFF-1025-00015B Independent Research Fund Denmark (IRFD or DFF)