DNA Damage Signaling - induced Cancer Cell Reprogramming as a Driver of Tumor Relapse
Dr Dmitry BULAVIN
Institute for Research on Cancer and Aging (IRCAN), Nice, France
vendredi 03 novembre 2017 - 10h30
- Salle de réunion 3013, ICS
Invité(e) par Génomique fonctionnelle et cancer, Irwin DAVIDSON
Accumulating evidence supports the role of the DNA damage response (DDR) in the negative regulation of tumorigenesis. Inactivation of WIP1 phosphatase, as a means of activating DDR signaling, delays tumor onset in multiple models but unexpectedly also accelerates tumor relapse. DDR signaling initiates a series of epigenetic reprogramming events resulting in activation of pro-tumorigeneic genes but can go as far as reactivation of the pluripotency gene Oct4a. Using genetic lineage tracing experiments and a novel labeling approach, we show that DDR-induced epigenetic reactivation of Oct4a regulates the resistance to chemotherapy and contributes to tumor relapse both in mouse and primary human cancers. In turn, deletion of Oct4a reverses chemoresistance and delays the relapse. Here, we uncovered an unexpected tumor-promoting role of DDR in cancer cell reprogramming providing novel therapeutic entry points for cancer intervention strategies.