Abstract A015: Aging limits stemness and tumor development in the lung by reprogramming iron homeostasis
Authors: Zhuang Xueqian , Wang Qing , Joost Simon , Ferrena Alexander , Blum Melissa , Krause Klavdija , Li Zhuxuan , Zheng Deyou , Wong Emily S , Tammela Tuomas 
Published: November 2024

Abstract
Aging is the most important and well-recognized risk factor for cancer. Aging leads to systemic decline of physical fitness, significantly changing the macroenvironment from the early tumor initiation to the terminal stage of metastasis. However, the underlying mechanisms only start to emerge. Here, using physiologically aged autochthonous genetically engineered mouse models (GEMMs) and primary cells, we demonstrate that aging suppresses lung cancer initiation and progression by degrading stemness of the alveolar cell of origin. Using single-cell transcriptomics, we uncover a distinct compositional landscape of cancer cell subsets in aged lung tumors, revealing a delay in the molecular progression of the lung lesions and an age-specific gene expression signature. Interestingly, key components of this gene signature were traced back to the aged cell of origin. Furthermore, the age-specific signature derived from GEMMs was predictive of patient age in human lung cancer, indicating conservation of the age-associated changes across species. Interestingly, our preliminary data suggested that tumor cells derived from aged tumor-bearing mice displayed higher metastatic potential, indicating that different mechanisms may govern tumor initiation and metastasis. Functional interrogation of the age-specific gene signature revealed that the loss of stemness and tumorigenic capacity is underpinned by aging-associated induction of the transcription factor NUPR1. We find that NUPR1 is induced in the cell of origin in aged mice and humans, which leads to a functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1 or iron supplementation restores stemness and promotes tumorigenic potential of aged alveolar cells. Conversely, targeting NUPR1 is detrimental to young alveolar cells by promoting ferroptosis. We find that aging-associated DNA hypomethylation at specific enhancer sites results in elevated NUPR1 expression, which is recapitulated in young cells by inhibition of DNA methylation. We uncover that, unlike the young, aged alveolar cells are functionally iron insufficient, which leads to loss of stemness and resistance to ferroptosis. Our results indicate that aging-associated reprogramming of the cell of origin determines tumor initiation potential, alters trajectory of tumor evolution and produces age-dependent vulnerabilities. These findings demonstrate that aging fundamentally changes the biology of lung cancer, shedding light on novel therapeutic modulation of cellular iron homeostasis or ferroptosis in regenerative medicine and in cancer prevention for the elderly population.
Citation Format: Xueqian Zhuang, Qing Wang, Simon Joost, Alexander Ferrena, Melissa Blum, Klavdija Krause, Zhuxuan Li, Deyou Zheng, Emily S Wong, Tuomas Tammela. Aging limits stemness and tumor development in the lung by reprogramming iron homeostasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A015.