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0The research investigates how physiological ageing reshapes the evolutionary trajectory of KRAS-driven lung adenocarcinoma, revealing that older subjects experience reduced primary tumor growth but a significantly accelerated rate of metastatic dissemination. Through comprehensive transcriptomic and epigenomic analyses, the study demonstrates that tumor cells in aged environments exhibit persistent activation of the integrated stress response (ISR) driven by the master transcriptional effector ATF4. This age-associated ATF4 signaling axis confers crucial epithelial-mesenchymal transition (EMT) traits, enhanced cellular plasticity, and metabolic rewiring that heavily relies on glutamine anaplerosis for survival. Consequently, targeting this metabolic vulnerability genetically or pharmacologically using glutaminase inhibitors effectively abolishes metastatic dissemination without impairing primary tumor growth. These findings establish ATF4 as both a necessary and sufficient driver of ageing-induced metastasis, offering a promising therapeutic opportunity for older patients with lung cancer.
References:
Patel A A H, Dzanan J J, Ali K X, et al. Ageing promotes metastasis via activation of the integrated stress response[J]. Nature, 2026, 652(8112): 1339-1348.
