Complement activation at the interface between adipocytes and cancer cells drives tumor progression

Area of Science:

• Oncology
• Cell Biology
• Cancer Metastasis

Background:

• The omentum is a frequent site for ovarian cancer (OC) metastasis.
• Adipocyte-cancer cell interactions promote an invasive and prometastatic phenotype in OC.

Purpose of the Study:

• To investigate the molecular mechanisms of cancer cell-adipocyte crosstalk in OC metastasis.
• To identify key pathways and molecules involved in adipocyte-driven OC progression.

Main Methods:

• Direct coculture of immortalized human visceral nondiabetic pre-adipocytes (VNPADs) with OC cells.
• RNA sequencing to analyze transcriptomic changes in cocultured OC cells.
• In vitro functional assays and in vivo tumor progression models.
• Analysis of complement C3 and C5 protein expression and function.

Main Results:

• Cocultured OC cells exhibited increased proliferation, invasiveness, and cisplatin resistance compared to monocultured cells.
• Significant transcriptomic changes were observed, with enriched pathways including PI3K/AKT and complement activation.
• Lipid transfer from adipocytes induced upregulation of complement C3 and C5 proteins in OC cells.
• Inhibition of C3/C5 reversed invasiveness, and C3 knockdown reduced tumor progression in vivo.
• Increased C3 expression was found in omental implants and OC ascites from high-BMI patients.
• C3 upregulation involved the ATF4-mediated integrated stress response (ISR).

Conclusions:

• Adipocyte-cancer cell interactions promote OC invasiveness and tumorigenesis.
• Lipid transfer, ISR activation, and complement C3/C5 upregulation are key mechanisms.
• Targeting these pathways may offer therapeutic strategies for OC metastasis.