Grant: Project Grant

Stem cells are the cells that can replenish themselves or differentiate, and they generate and maintain all tissue-specific functions in adults. Stem cells share certain properties in common with tumor cells, including shortened chromosome ends (telomeres) with age, and age-associated non-genetic changes (called the epigenetic state). We recently discovered that stem cells or cancer cells with short telomeres are also hypersensitive to DNA damage and to proper DNA replication progression. Our data suggest these properties are linked, and can be modified to improve cell function during aging, or to target cancer cells with short telomeres. We will pursue these ideas with 3 aims: 1) We will investigate the genes and gene networks that lead to the defective ability of stem cells with eroded telomeres to differentiate, and probe how modulations of these networks may restore stable cell fate commitment. 2) We will determine whether an elevated response to DNA damage leads to increased lethality in tumor cells with short telomeres, and how these genetic alterations affect the genome-wide epigenetic state. We will also test if reducing this enhanced DNA damage response in tumor cells might alter their epigenetic state and improve their response to differentiation therapy. 3) Using vivo cell-tracing and cell clearance strategies, we will test if we can remediate the defects that arise due to eroded telomeres to reduce tumor formation and improve tissue health. We have uncovered that cells with short telomeres are more sensitive to disruptions in DNA integrity and replication. Building on these new results, we will undertake a comprehensive investigation of this vulnerability in stem cells and cancer cells with short telomeres. Since cancer cells and stem cells rely on telomerase for their proliferation and function, the ability to manipulate these vulnerabilities may provide means to improve tissue function, or to impair cancer cell survival and tumor formation.