Senescence associated inflammasome (SAI) activation promotes cancer progression (TUM4P.909)

Abstract

Abstract Oncogene-induced senescence functions as a barrier against cell transformation and tumorigenesis. Paradoxically, recent studies indicate that senescence also promotes tumor progression through secretion of inflammatory molecules or senescence-associated secretory phenotype (SASP). However, the signaling pathways leading to SASP and the interaction between senescent cells and innate immune cells are poorly understood. Utilizing human and murine breast cancer cells, as well as breast cancer mouse models, this study demonstrates that senescence-associated inflammasome (SAI) generate a positive feedback loop to propagate inflammation through interaction with innate immune cells, contributing to the tumor development. Our data show that cellular senescence induced by oncogenes, such as K-Ras12V and Her2/ERBB2, led to inflammasome activation and IL-1beta production in both murine and human breast cancer cells. Notably, we found that blocking inflammasome activity could suppress both IL-1beta production and oncogene-induced senescence in breast cancer cells. Our results further show that the crosstalk between senescent cells and innate immune cells promoted inflammation and breast cancer progression. Together, our findings demonstrate a critical role for the senescence-associated inflammasome in oncogenic inflammation and tumor development.