Ageing promotes metastasis via activation of the integrated stress response - PubMed
12 hours ago
- #ageing
- #metastasis
- #lung cancer
- Ageing reprograms the evolutionary trajectory of KRAS-driven lung adenocarcinoma, limiting primary tumour growth but promoting metastasis.
- Epigenetic activation of the integrated stress response (ISR) and its effector ATF4 drives epithelial and metabolic plasticity, enabling metastatic competence.
- Aged tumour cells show increased sensitivity to the PERK-eIF2α arm of the unfolded protein response, leading to persistent ATF4 signalling.
- Targeting ISR-ATF4 genetically or pharmacologically can limit metastasis, while ATF4 overexpression alone induces metastasis.
- The ageing-ATF4 axis creates a dependency on glutamine metabolism, revealing a therapeutic vulnerability.
- Clinical data show ATF4 is enriched in aged tumours and correlates with poor survival and advanced-stage disease.