A non-complement role for C1R rewires integrin and death-receptor signaling to drive renal cancer metastasis

BACKGROUND: Metastasis is the leading cause of death in clear cell renal cell carcinoma (ccRCC) patients. Anoikis, a form of programmed cell death induced by the loss of cell-extracellular matrix interactions, is a critical factor in hindering metastasis. Nevertheless, the regulatory mechanisms underlying anoikis resistance in ccRCC remain poorly characterized and warrant further investigation. METHODS: We created a single-cell transcriptomic atlas of ccRCC metastasis and used multi-omics data to identify the key role of complement C1R during metastasis. Anoikis-related cell experiments and mouse models were conducted to assess the impact of C1R on anoikis resistance and metastatic potential. Transcriptome sequencing, immunoprecipitation, molecular docking, truncation construction, and immunofluorescence were used to explore how C1R induces anoikis resistance. The mouse lung metastasis model was employed to validate the efficacy of a novel combination drug regimen. RESULTS: Our study identifies complement C1R as a crucial regulator of ccRCC metastasis by enhancing anoikis resistance. ITGB1 and FAF1 have been recognized as crucial downstream targets of C1R. Specifically, C1R promotes anoikis resistance by facilitating ITGB1 endocytosis to activate the Akt/Erk pathway and by inhibiting FAF1-FAS binding to block the Fas/FasL pathway. Moreover, our findings indicate that the combined use of the ITGB1 inhibitor (ATN161) and the Fas/FasL pathway activator (Edelfosine) significantly suppresses ccRCC metastasis. CONCLUSION: C1R functions as a pivotal driver of ccRCC metastasis through dual mechanisms, and therapeutic strategies targeting C1R may offer a promising approach to inhibit metastasis.