Ecological network analysis reveals cancer-dependent chaperone-client interaction structure and robustness in the mitochondria

Abstract

Cancer cells alter the expression levels of metabolic enzymes to fuel proliferation. The mitochondrion is a central hub of metabolic reprogramming, where multiple chaperons service hundreds of clients, forming complex chaperone-client interaction networks (CCINs). Studying (i) how network structure varies across cancer types and (ii) the influence of structure on networks robustness to chaperon targeting is key to developing cancer-specific drug therapy. We investigate these yet unaddressed questions using theory and methodology from network ecology. We show that CCINs are non-randomly structured across cancer types. Moreover, we identify groups of chaperones that interact with similar clients, providing specialization on clients but also redundancy in the case of chaperone removal on the other. Simulations of network robustness show that this modular structure strongly affects cancer-specific response to chaperon removal. Our results open the door for new hypotheses regarding the ecology and evolution of CCINs and can inform caner-specific drug development strategies.