ΔNp63γ/SRC/Slug Signaling Axis Promotes Epithelial-to-Mesenchymal Transition in Squamous Cancers

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Epithelial-to-mesenchymal transition (EMT) is crucial for tumor invasion in head and neck squamous cell carcinoma (HNSCC).
• Understanding the regulatory pathways of EMT in HNSCC is essential for developing targeted therapies.

Purpose of the Study:

• To investigate the regulation of EMT in HNSCC.
• To identify key effectors and upstream regulatory pathways involved in HNSCC invasion.

Main Methods:

• Utilized a three-dimensional organotypic raft culture model.
• Employed bioinformatic analysis and immunohistochemistry (IHC) on patient samples.
• Conducted splice-form-specific depletion and rescue experiments.

Main Results:

• Identified SNAI2 (Slug) as a critical effector of EMT downstream of TP63 overexpression in HNSCC.
• The ΔNp63γ isoform was found to activate the SRC signaling axis and SNAI2-mediated EMT and invasion.
• Elevated SRC levels correlated with poor patient outcomes in HNSCC, and SRC inhibition reversed EMT and invasion.

Conclusions:

• Overexpression of ΔNp63γ drives HNSCC cell invasion via SRC-Slug-mediated EMT.
• This process is targetable, as SRC signaling inhibitors can reverse EMT and invasion.
• Findings suggest SRC inhibitors as a potential therapeutic strategy for HNSCC.