Serpin Facilitates Tumor-Suppressive Cell Competition by Blocking Toll-Mediated Yki Activation in Drosophila

Area of Science:

• Cell biology
• Developmental biology
• Cancer research

Background:

• Normal epithelial tissues possess inherent tumor-suppressive capabilities.
• Oncogenic cells, such as those with mutations in scribble (scrib) or discs large (dlg), are typically eliminated by cell competition in Drosophila imaginal epithelium.

Purpose of the Study:

• To identify factors involved in the elimination of oncogenic cells from normal epithelium.
• To elucidate the molecular mechanisms underlying cell competition against pre-malignant cells.

Main Methods:

• Genetic screening in Drosophila to identify novel regulators.
• Analysis of Toll signaling pathways and their role in cell competition.
• Investigating the Hippo pathway and its effectors in oncogenic cell overgrowth.

Main Results:

• Serpin5 (Spn5), a negative regulator of Toll signaling, was identified as crucial for eliminating scrib mutant clones.
• Downregulation of Spn5 in normal cells elevates Toll signaling in neighboring scrib cells.
• Activation of Toll signaling in scrib cells promotes their overgrowth by activating JNK, F-actin, and the Hippo pathway effector Yorkie, blocking cell death and promoting proliferation.

Conclusions:

• Spn5 acts as an extracellular surveillance factor, facilitating the elimination of pre-malignant cells.
• Toll signaling plays a critical role in determining the fate of oncogenic cells within an epithelium.
• Dysregulation of Spn5 and Toll signaling can lead to tumorous overgrowth, highlighting a novel mechanism in cancer suppression.