DNA Damage Signaling - induced Cancer Cell Reprogramming as a Driver of Tumor Relapse

Accumulating evidence supports the role of the DNA damage response (DDR) in the negative regulation of tumorigenesis. Previous data show that inactivation of WIP1 phosphatase, as a means of activating DDR signaling, delays tumor onset in multiple mouse models. Unexpectedly, we found that targeting WIP1 also accelerates tumor relapse. Through chromatin remodeling, DDR signaling poises the reactivation of early pluripotency genes, including OCT4A, contributing to tumor relapse. Redistribution of DNMT3B to heterochromatic sequences appears to be a key initiating event in DDR-dependent OCT4 locus reactivation. However, full reactivation requires the presence of a driving oncogene such as Myc and macroH2A downregulation, both of which are commonly present in advanced human cancers. Using genetic lineage tracing experiments, we further showed that Oct4a-expressing cells contributed to tumor relapse. Furthermore, conditional deletion of Oct4a was sufficient to significantly delay the relapse of myc-driven B-cell lymphomas. Here, we have uncovered an unexpected tumor-promoting role of DDR signaling in enforcing oncogene-induced tumor relapse by poising cancer cell reprogramming into a stemness-like state. Our data support a model in which clonal evolution serves as an alternative organizational structure of certain tumors, such that nearly any cancer cell may acquire novel epigenetic traits to facilitate tumor relapse without necessarily committing to a Cancer Stem Cell model. Gene expression analysis in human HCT116 cells (WT), WT treated with ATM inhibitor (WT+ ATMi), WIp1-depleted HCT116 cells with shRNA(SH) and SH treated with ATM inhibitor (SH + ATMi). Total RNA was purified from indicated cancer cell lines of 3 different biological replicate for each cell line, to assess differently expressed genes beween all cell line analyzed