The Splicing Factor SF2 Is Critical for Hyperproliferation and Survival in a TORC1-Dependent Model of Early...

Area of Science:

• Cell Biology
• Molecular Oncology
• Developmental Biology

Background:

• The Target of Rapamycin complex 1 (TORC1) pathway regulates cell growth and is hyperactivated in many cancers.
• TORC1 inhibitors face limitations due to side effects and resistance, necessitating alternative therapeutic strategies.
• Identifying downstream effectors of TORC1 is crucial for developing targeted cancer therapies.

Purpose of the Study:

• To identify key modulators or downstream effectors of TORC1 signaling that limit aberrant cell growth in cancer.
• To investigate the role of serine/arginine-rich splicing factor 2 (SF2) in Pten-mutant Drosophila epithelial tissues.
• To explore SF2 as a potential therapeutic target for tumors with elevated TORC1 activity.

Main Methods:

• Utilized Drosophila epithelial tissue models with Pten mutations to study hyperproliferation.
• Performed knockdown of candidate TORC1 signaling network factors, including SF2.
• Conducted transcriptomics analysis to identify SF2-regulated transcripts, such as p53, in tumor contexts.

Main Results:

• SF2 was identified as the most limiting factor for the overgrowth of Pten-mutant tissues.
• SF2 knockdown induced apoptosis specifically in Pten-mutant cells, leaving control tissues unaffected.
• SF2 functions downstream or in parallel to TORC1, independent of S6K activation, and regulates alternative splicing of transcripts including p53.

Conclusions:

• SF2 plays a critical role in limiting the proliferation of Pten-deficient cells, suggesting a specific vulnerability in these tumor models.
• SF2's regulation of alternative splicing, including p53, highlights its complex role in tumor progression.
• SF2 emerges as a promising and specific therapeutic target for cancers characterized by hyperactive TORC1 signaling.