Wnt activation disturbs cell competition and causes diffuse invasion of transformed cells through NF-κB-MMP21 pathway

Area of Science:

• Cell biology
• Cancer research
• Molecular oncology

Background:

• Normal epithelial cells eliminate RasV12-transformed cells via cell competition.
• Factors compromising cell competition and driving carcinogenesis are not fully understood.

Purpose of the Study:

• Investigate how sequential gene mutations affect RasV12-induced cell competition in intestinal epithelial tissues.
• Elucidate the mechanisms behind compromised cell competition and cancer development.

Main Methods:

• Utilized RasV12-transformed intestinal epithelial models.
• Analyzed gene mutations mimicking multi-sequential carcinogenesis.
• Assessed cell extrusion directionality and invasion.
• Investigated MMP21 and NF-κB signaling pathways.
• Examined human colorectal carcinoma samples.

Main Results:

• Wnt-activated epithelia reversed RasV12 cell extrusion direction, leading to basal delamination via MMP21 upregulation.
• Upregulated MMP21, partly mediated by NF-κB signaling, promoted invasive carcinoma development.
• Blocking NF-κB signaling restored apical elimination of RasV12 cells.
• The NF-κB-MMP21 axis was significantly elevated in early human colorectal carcinoma.

Conclusions:

• Sequential mutations can reprogram cell competition, favoring transformed cell invasion.
• The NF-κB-MMP21 axis is a critical pathway in RasV12-induced carcinogenesis and colorectal cancer.
• Targeting this axis may offer therapeutic strategies for preventing cancer invasion.