Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis

Area of Science:

• Cellular biology
• Cancer research
• Aging research

Background:

• Aging diminishes adult stem cell number and function.
• The hypothesis that reduced stemness suppresses tumorigenesis lacks in vivo validation.
• Understanding age-related stem cell changes is crucial for cancer prevention.

Purpose of the Study:

• To investigate how aging affects lung cancer initiation and progression in vivo.
• To elucidate the molecular mechanisms, including the role of stemness and iron homeostasis.
• To explore therapeutic strategies targeting age-related cancer suppression.

Main Methods:

• Utilized physiologically aged autochthonous genetically engineered mouse models and primary cells.
• Investigated the role of the transcription factor NUPR1 and lipocalin-2 in aged alveolar cells.
• Assessed the impact of genetic inactivation of the NUPR1-lipocalin-2 axis and iron supplementation.
• Examined DNA methylation patterns and ferroptosis induction.

Main Results:

• Aging suppresses lung cancer initiation and progression by reducing alveolar stem cell stemness.
• The NUPR1-lipocalin-2 axis induces functional iron insufficiency in aged cells, impairing stemness.
• Genetic targeting or iron supplementation rescued stemness and tumorigenic potential in aged cells.
• Targeting this axis in young cells induced ferroptosis, while aged cells showed ferroptosis resistance.

Conclusions:

• Aging-associated functional iron insufficiency, mediated by NUPR1 and lipocalin-2, leads to stemness loss and suppressed tumorigenesis.
• Therapeutic modulation of iron homeostasis offers potential for regenerative medicine and cancer prevention.
• Cancer prevention strategies should consider targeting younger individuals, as most cancers initiate early in life.