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

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Malignant tumors often exhibit necrosis, leading to an inflammatory response that can promote tumor progression.
• The specific impact of necrotic debris, or damage-associated molecular patterns (DAMPs), on tumor cell behavior remains largely uncharacterized.
• Understanding these interactions is crucial for developing novel anti-cancer therapies.

Purpose of the Study:

• To investigate the effect of DAMPs on Ewing sarcoma (EwS) cells in both 2D and 3D culture models.
• To elucidate the underlying mechanisms by which DAMPs influence tumor growth, focusing on cholesterol homeostasis.
• To explore the therapeutic potential of modulating the STING (stimulator of interferon genes) pathway and cholesterol synthesis in EwS.

Main Methods:

• Primary EwS cells and cell lines were cultured in 2D and 3D (spheroid) formats.
• Cells were treated with DAMPs and/or cyclic GMP-AMP (cGAMP), a STING ligand.
• Cholesterol levels, tumor cell proliferation, and tumor-initiating capacity were assessed.
• The effects of simvastatin, a cholesterol synthesis inhibitor, were evaluated in combination with STING modulation.

Main Results:

• DAMPs significantly promoted the growth of EwS spheroids but not 2D cultures.
• This growth promotion was associated with an increased cholesterol load within the spheroids.
• Stimulation of STING with cGAMP decreased tumor cell cholesterol and reduced tumor-initiating ability.
• Overexpression of STING or cGAMP treatment counteracted the DAMPs-induced growth promotion and synergized with simvastatin to inhibit tumor growth.

Conclusions:

• Modulation of cholesterol homeostasis is a key mechanism by which necrotic debris and STING signaling impact tumor growth.
• STING agonists can oppose the pro-tumorigenic effects of DAMPs by regulating cholesterol levels.
• Combining STING agonists with cholesterol synthesis inhibitors like simvastatin presents a promising therapeutic strategy for controlling Ewing sarcoma growth.