Necrotic debris and STING exert therapeutically relevant effects on tumor cholesterol homeostasis

Necrosis is a common feature of most solid malignant tumors and a major consequence of chemotherapy. The debris released by necrotic cells includes many damage/danger-associated molecular patterns (DAMPs) that stimulate cell surface and intracellular pattern recognition receptors (PRRs) activation. Treatment of Ewing's sarcoma with conventional chemotherapy has reached a plateau in efficacy. The inability to target the fusion protein responsible for its pathogenesis warrants the quest for alternative therapeutic strategies. We have shown that DAMPs released by necrotic cells can stimulate the growth of EwS cells cultured in 3D and that of the related tumors in vivo. In stark contrast, we observed that STING, a signaling platform that responds to nucleic acids released from damaged nuclei, opposed the effect of DAMPs on EwS cell growth in vitro and tumor growth in vivo, maintaining cholesterol homeostasis. Our observations suggest that STING activation in conjunction with cholesterol-reducing agents may offer an unsuspected approach to control EwS growth. Overall design: Total Two samples of primary Ewing sarcomas, plus A673 cell line in spherogenic and adherent cultures: cGAMP, shRNA, DAMPs treatments.