Abstract

Senescent cells, or cells that have irreversibly stopped dividing and which secrete inflammatory signals, accumulate in both aged tissues and tumors. Senescent cell accumulation is both a hallmark of aging tissues and can promote tumorigenesis in some contexts. It remains unclear why senescent cells persist in many aged tissues and tumors, despite sending signals that recruit immune cells such as macrophages, which can clear senescent cells via phagocytosis. This project aims to apply powerful genetic tools to investigate the molecular basis of senescent cell accumulation and resistance to macrophage clearance, using senescent lung tumor cells as a model. We will test the overarching hypothesis that senescent tumor cells suppress their clearance by macrophages by expressing anti-phagocytic factors that engage specific macrophage receptors. To uncover the factors that govern senescent cell resistance to macrophage clearance, we will apply a combination of functional genomic screens, live-cell imaging, and in vivo tumor models. Our work may potentiate therapeutic strategies that stimulate immune clearance of senescent cells by targeting the novel signaling axes we expect to uncover.