Dpp and Immune Response Pathways Factors Mediate Paracrine Induction of Senescent Cells in Drosophila

Abstract

Transition toward senescence is a cellular response to different stressors like ionizing radiation, telomere shortening or oncogene activation. This phenomenon is evolutionarily conserved across species, from insects to humans. Senescent cells (SCs) permanently withdraw from the cell cycle and undergo a series of physiological changes, most notably the acquisition of a robust secretory activity characterized by the release of numerous molecules, including cytokines, chemokines, and metalloproteinases. Through this program, termed Senescence-Associated Secretory Phenotype (SASP), SCs actively communicate with and influence their microenvironment. In mammalian tissues the number of SCs increases with age and their accumulation has been proposed to contribute to several age-associated pathologies. Studies in vertebrate systems have demonstrated that new SCs can arise through paracrine signaling from pre-existing SCs, a process that requires the activity of Transforming Growth Factor {beta} (TGF-{beta}). We have investigated the phenomenon of paracrine recruitment of SCs in the Drosophila wing disc. Our results show that an initial stress event induces a primary wave of SCs, comprising approximately 10% of the target cell population. Subsequently, a second wave of SCs emerges through paracrine signaling from the initial cohort, increasing the overall proportion of SCs to about 24%. The formation of this second wave is mediated by the growth factor Decapentaplegic (Dpp), the Drosophila ortholog of TGF-{beta}. Dpp activates a non-canonical signaling route in non-SCs, driving their conversion to a senescent state. This novel branch of the Dpp pathway engages several components of the innate immune response. Collectively, these findings underscore the evolutionary conservation of senescence-associated signaling networks and suggest that paracrine amplification of senescence may play a role in tumorigenesis and age-related diseases.