Injury prevents Ras mutant cell expansion in mosaic skin

Area of Science:

• Dermatology
• Oncology
• Cell Biology

Background:

• Healthy skin comprises a mix of normal (wild-type) and mutated cells.
• Oncogenic Ras proteins can drive tumor formation, especially when combined with skin injury.

Purpose of the Study:

• To investigate how skin injury affects the balance between wild-type and oncogenic Ras-mutated cells in genetically mosaic skin.
• To elucidate the mechanisms underlying cell competition in response to injury in this context.

Main Methods:

• Utilized genetically mosaic mouse models with oncogenic Ras mutations (HrasG12V/+ and KrasG12D/+).
• Analyzed cell proliferation and competition dynamics in both uninjured and injured skin.
• Investigated the role of the epidermal growth factor receptor (EGFR) pathway and p21 (a cell cycle inhibitor) in regulating cell competition.

Main Results:

• In uninjured skin, Ras-mutated cells outcompete wild-type cells.
• Following injury, wild-type cells proliferate more, suppressing the expansion of Ras-mutated cells.
• This switch is driven by differential activation of the EGFR pathway, where wild-type cells respond to EGFR ligands, unlike Ras-mutated cells.
• EGFR inhibition or increased wild-type cell proliferation (via p21 loss) reversed this protective effect.

Conclusions:

• Skin injury shifts the competitive balance, favoring wild-type cells over oncogenic Ras-mutated cells.
• The EGFR pathway plays a critical role in mediating this injury-induced competitive switch.
• Understanding this dynamic is crucial for comprehending skin tumorigenesis in mosaic tissues.