Aging promotes lung cancer metastasis through epigenetic ATF4 induction

Abstract Lung cancer is primarily a disease of the elderly. Despite shared molecular changes between aging and cancer 1 – such as permissive chromatin states and deregulated protein homeostasis – studies on physiologically aged models of human lung cancer are lacking. Here, we show that aging alters the progression of KRAS-driven non-small cell lung cancer (NSCLC), promoting metastasis while suppressing primary lung tumor growth. Clinically, a multicenter analysis of all consecutively diagnosed NSCLC cases in Western Sweden over a 3-year period confirmed increased metastasis and smaller primary tumor size with age in KRAS-driven NSCLC. In addition, primary lung tumor cultures derived from older mice demonstrated an increased metastatic phenotype. Unbiased transcriptomic and epigenomic analyses identified ATF4, a major arm of the unfolded protein response (UPR), as a driver of aging-induced lung cancer metastasis. Furthermore, we found that the age-associated increase in ATF4 fuels metastatic dissemination through metabolic rewiring, including increased glutaminolysis. Finally, we report that pharmacological inhibition of glutaminase effectively suppressed aging-induced metastasis. Our findings suggest a novel adjuvant therapy for human lung cancer by targeting aging-induced metabolic plasticity, highlighting the need to consider the biology of aging in the development of cancer therapy.