Séminaire IBS : Uncovering moonlighting functions of complement C1r in kidney cancer through integrative multi-omics

Par Dr Nicolas Merle (Équipe Inflammation, complément et cancer, Centre de recherche des Cordeliers, Paris

Complement proteins, classically viewed as plasma-derived immune sentinels, are now emerging as key intracellular regulators of metabolism and cell homeostasis. In clear cell renal cell carcinoma (ccRCC), our lab previously demonstrated that complement activity occurs within tumor cells and operates independently of the canonical extracellular cascade. In particular, high expression of the C1R gene correlates with poor prognosis, and data mining of public scRNA-seq and spatial datasets revealed that C1r is locally produced by both tumor cells and cancer-associated fibroblasts.

Unexpectedly, C1r appears to function intracellularly, modulating tumor cell proliferation and migration independently of complement activation. To explore the molecular underpinnings of this non-canonical role, we performed subcellular fractionation and multiplex immunofluorescence imaging (6-marker panel) to localize C1r across cellular compartments. Co-immunoprecipitation followed by mass spectrometry identified 36 potential intracellular binding partners of C1r.

Cross-referencing the interactome with transcriptomic pathway analyses highlighted a previously unreported candidate interactor belonging to the collagen family. Spatial transcriptomic data from ccRCC patient tissues revealed that C1R and the candidate partner display tightly correlated spatial expression patterns, suggesting a co-regulated expression and potential interaction within the tumor microenvironment.

These findings raise the intriguing possibility that C1r engages in intracellular, non-proteolytic functions via novel protein-protein interactions in ccRCC. While the biological significance of this candidate interaction remains under investigation, our results support a broader reconsideration of complement proteins as structural and signaling regulators within cancer cells.

Hôte : Christine Gaboriaud (IBS/Groupe Complement, anticorps et maladies infectieuses)