Endocrine Abstracts

Oncogenic activation and anticancer therapies are known to evoke – especially if apoptotic cell death is no longer available – cellular senescence as another stress-responsive safeguard and ultimate cell-cycle exit program in (pre-)malignant cells. Hence, oncogene-induced senescence (OIS) and therapy-induced senescence (TIS) are considered to operate as important anti-tumor principles. However, we previously reported (Dörr-JR et al., Nature, 2013) that secondary, ‘senolytic’ elimination of TIS cancer cells improves long-term outcome to therapy, thereby suggesting that lastingly persistent senescent cells might be harmful. Driven by the intriguing overlap of numerous pathway mediators relevant in both stem cell and senescence signaling, we now observed in lymphoma and other cancer types reprogramming of senescent cancer cells into a latent adult tissue stem cell state. Strikingly, these senescent cells exerted their gained stemness upon enforced or spontaneous cell-cycle re-entry out of senescence. As the pivotal underlying mechanism, we identified epigenetic reprogramming into a permissive state for active Wnt signaling, which is maintained in a small but stable fraction of the tumor cells post-senescence. Exploiting a non-stem bulk leukemia model, we found cells incapable of re-initiating the disease to convert into leukemia stem cells via temporarily entering TIS. In this late-breaking presentation, strategies to induce or restore senescence in the first place, and conceptually novel approaches to selectively eliminate these senescent cancer cells subsequently for improved long-term tumor control will be presented and discussed.