PT  - JOURNAL ARTICLE
AU  - Sampath Katakam
AU  - Santosh Anand
AU  - Patricia Martin
AU  - Nicolo Riggi
AU  - Ivan Stamenkovic
TI  - Necrotic debris and STING exert therapeutically relevant effects on tumor cholesterol homeostasis
AID  - 10.26508/lsa.202101256
DP  - 2022 Mar 01
TA  - Life Science Alliance
PG  - e202101256
VI  - 5
IP  - 3
4099  - https://www.life-science-alliance.org/content/5/3/e202101256.short
4100  - https://www.life-science-alliance.org/content/5/3/e202101256.full
SO  - Life Sci. Alliance2022 Mar 01; 5
AB  - 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.