Abstract
Malignant tumors commonly display necrosis, which invariably triggers an inflammatory response that supports tumor growth. However, the effect on tumor cells of necrotic debris, or damage-associated molecular patterns (DAMPs) released by dying cells is unknown. Here, we addressed the effect of DAMPs on primary Ewing sarcoma (EwS) cells and cell lines grown in 3D (spheroids) and 2D culture. We show that DAMPs promote the growth of EwS spheroids but not 2D cultures and that the underlying mechanism implicates an increase in cholesterol load in spheroids. In contrast, stimulation of the nucleic acid sensor signaling platform STING by its ligand cyclic GMP-AMP decreases the tumor cell cholesterol load and reduces their tumor initiating ability. Overexpression of STING or stimulation with cyclic GMP-AMP opposes the growth stimulatory effect of DAMPs and synergizes with the cholesterol synthesis inhibitor simvastatin to inhibit tumor growth. Our observations show that modulation of cholesterol homeostasis is a major effect of necrotic cell debris and STING and suggest that combining STING agonists with statins may help control tumor growth.
Highlights
Necrosis is a common feature of most solid malignant tumors and a major consequence of chemotherapy
We have shown that danger-associated molecular patterns (DAMPs) released by damaged cells undergoing necrosis can stimulate the growth of Ewing sarcoma (EwS) spheroids as well as that of the corresponding tumors in vivo
Upon interrogation of the possible mechanisms that underlie DAMP-mediated enhancement of EwS growth, we discovered that, similar to their effect on immune cells, DAMPs stimulate EwS cells to express a host of cytokines and chemokines implicated in inflammation
Summary
Necrosis is a common feature of most solid malignant tumors and a major consequence of chemotherapy. Recent work has shown that by expressing phosphatidylserine on their surface, apoptotic cell debris can stimulate macrophage activation and cytokine production, thereby contributing to tumor growth [10]. Their growth promoting effect could be inhibited by resolvins [10]. Similar to apoptotic bodies, necrotic cell-derived DAMPs may stimulate tumor growth indirectly by contributing to the generation of an inflammatory TME, they may affect tumor cell behavior directly, as tumor cells express a variable repertoire of PRRs. the effect of DAMPs on tumor cells is relatively unexplored
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