Age-associated inflammation connects RAS-induced senescence to stem cell dysfunction and epidermal malignancy

Area of Science:

• Oncology
• Immunology
• Dermatology
• Aging Research

Background:

• Aging is the primary risk factor for cancer development.
• Non-melanoma skin cancers are common age-associated malignancies.
• Mutant H-Ras activation is frequent in cutaneous squamous cell carcinoma (SCC).

Purpose of the Study:

• To investigate the differential effects of H-Ras activation on young versus aged mouse skin.
• To explore the role of aging, inflammation, immune response, and cell senescence in skin cancer progression.

Main Methods:

• Induction of mutant H-Ras in mouse epidermis.
• Comparative analysis of young and aged mouse skin responses.
• Assessment of hyperplasia, dysplasia, inflammation, immune cell infiltration, cell senescence, and gene expression (IL4/IL10, Pdl1).
• Evaluation of skin regeneration after oncogenic H-Ras inactivation.

Main Results:

• H-Ras activation in aged skin led to more dysplasia and progression to in situ SCC compared to young skin (hyperplasia).
• Aged skin showed increased inflammation, immune cell accumulation (T cells, macrophages, mast cells), and cell senescence.
• An age-dependent increase in pro-inflammatory mediators, enhanced IL4/IL10 expression, and a Th2 immune skewing were observed.
• Aged skin exhibited increased Pdl1 expression, promoting immune evasion.
• Young skin regenerated upon H-Ras inactivation, while aged skin failed to repair, indicating aged epidermal stem cell dysfunction.

Conclusions:

• Aging exacerbates H-Ras-driven skin carcinogenesis through increased inflammation, immune suppression, and senescence.
• Aged epidermal stem cells show impaired regenerative capacity, contributing to failed tissue repair.
• Findings highlight an age-dependent link between senescence, immune infiltration, and cancer progression, explaining increased cancer risk in the elderly.