Tuomas Tammela at ARDD2025: Intersection of tumorigenesis and aging-associated decline in lung...

Tuomas Tammela presents his lab’s research on how aging affects tumorigenesis in the lung. Using genetically engineered mouse models of lung adenocarcinoma, they found that aged mice develop fewer and smaller tumors compared to young mice, contrary to expectations. This is due to a decline in the regenerative capacity of alveolar type 2 (AT2) cells, the cell of origin for most lung adenocarcinomas. The aged AT2 cells show reduced proliferation and plasticity, and this phenotype is retained in tumors that arise from them, suggesting a cellular memory. Transcriptomic and methylomic analyses revealed that many age-related gene expression changes are maintained in tumors, with DNA methylation playing a key role. They identified the transcription factor NUPR1 as a critical mediator: it is induced in aged AT2 cells and in tumors from older patients. NUPR1 drives iron insufficiency, making cells resistant to ferroptosis but impairing their growth and plasticity. Knocking out NUPR1 in aged mice rescues tumor progression but suppresses it in young mice, highlighting a context-dependent role. The same mechanism affects other stem cell types, such as intestinal stem cells. The findings suggest that cancer prevention efforts should focus on younger individuals, as the soil for transformation is more fertile then. The work also points to potential therapeutic strategies to rejuvenate aged stem cells by modulating iron levels.