Oncogenic Ras diverts a host TNF tumor suppressor activity into tumor promoter

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• The role of inflammatory cytokines, like tumor necrosis factor (TNF), in cancer is complex, exhibiting both pro-tumor and anti-tumor effects.
• Previous studies in Drosophila suggested TNF could eliminate cells lacking polarity tumor suppressors (dlg or scrib).

Purpose of the Study:

• To investigate the role of TNF signaling in Ras-driven tumors lacking the scrib tumor suppressor.
• To elucidate the mechanisms by which TNF signaling influences tumor malignancy and host survival in this context.

Main Methods:

• Utilized Drosophila models to study tumors deficient for the scrib tumor suppressor and expressing the Ras oncoprotein.
• Analyzed the impact of TNF signaling on tumor growth, invasive migration, and host survival.
• Investigated the source and function of TNF-expressed by tumor-associated hemocytes.

Main Results:

• In scrib-deficient tumors with Ras expression, TNF signaling shifted from a potential anti-tumor to a pro-tumorigenic role.
• TNF signaling enhanced tumor growth, caused larval arrest, and promoted invasive migration, signifying increased malignancy.
• Tumor-associated hemocytes were identified as the source of TNF, and their TNF expression was crucial for triggering TNF signaling in tumor cells.

Conclusions:

• Oncogenic Ras activation can reprogram TNF signaling within tumors, diverting it towards promoting malignancy.
• Tumors can evolve to hijack host immune responses, specifically TNF signaling from hemocytes, to enhance their own growth and invasiveness.
• This study highlights a mechanism by which tumors become malignant by co-opting TNF signaling pathways.