Aging promotes lung cancer metastasis through epigenetic ATF4 induction

Patel, A. A. H.; Dzanan, J.; Ali, K. X.; Eklund, E. A.; Alvarez, S. W.; Altinönder, I.; Raj, D.; Zowalaty, A. E. E.; Sayin, S. I.; Dankis, M.; Schwarz, M.; Jonasson, E.; Le Gal, K.; Albatrok, H.; Oloffson Bagge, R.; Härtlova, A.; Stahlberg, A.; Hallqvist, A.; Wiel, C.; Sayin, V. I.

doi:10.1101/2024.07.03.601209

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bioRxiv · 10.1101/2024.07.03.601209

Aging promotes lung cancer metastasis through epigenetic ATF4 induction

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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.

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Patel, A. A. H., Dzanan, J., Ali, K. X., Eklund, E. A., Alvarez, S. W., Altinönder, I., Raj, D., Zowalaty, A. E. E., Sayin, S. I., Dankis, M., Schwarz, M., Jonasson, E., Le Gal, K., Albatrok, H., Oloffson Bagge, R., Härtlova, A., Stahlberg, A., Hallqvist, A., Wiel, C., Sayin, V. I.. 2024-07-05. Aging promotes lung cancer metastasis through epigenetic ATF4 induction. https://doi.org/10.1101/2024.07.03.601209

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