Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of
premalignant pancreatic lesions

Objective: Cellular senescence limits tumorigenesis by blocking the proliferation of
premalignant cells. Additionally, however, senescent cells can exert paracrine effects
influencing tumor growth. It is currently unknown whether senolytic drugs, aimed at
eliminating senescent cells from lesions, could be beneficial in blocking tumor
development. Senescent cells are present in premalignant pancreatic intraepithelial
neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterized.
Design: To uncover the functions of senescent cells and their potential contribution to
early pancreatic tumorigenesis, we isolated and characterized senescent cells from
PanINs formed in a Kras-driven mouse model, and tested the consequences of their
elimination through senolytic treatment.
Results: We found that senescent PanIN cells exert a tumor-promoting effect through
expression of a pro-inflammatory signature that includes high Cox2 levels. Senolytic
treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent
cells, and an intermittent short-duration treatment course dramatically reduced PanIN
development and progression to pancreatic carcinoma.
Conclusions: These findings reveal that senescent PanIN cells support tumor growth and
progression, and provide a first indication that targeted senolytic elimination of senescent
cells may be effective as preventive therapy for the progression of precancerous lesions.