Cancer cells proliferate in an uncontrolled manner, inflicting replication stress and concomitant DNA damage due to impaired fork progression and fork stalling. Embryonal tumors such as neuroblastoma have retained the blueprint of the replicative stress resistance phenotype of (embryonic) stem cells, underscoring the therapeutic potential of the mediators of these pathways. Recently, we and others reported on the involvement of the chromatin remodeling protein PHF6 in fork restart, replication stress and DNA damage responses, through interactions with chromatin remodeling complexes as well as the ribonucleotide reductase subunit M2 (RRM2) and the nuclear pore complex. Further building upon recently gathered preliminary data, I propose to perform a detailed dissection of the poorly characterized epigenetic modifier PHF6 as a putative novel and key chromatin adaptor shaping the (epi)genetic landscape in neuroblastoma in functional concert with the nuclear pore. This interaction could play a significant role in emerging nuclear pore moonlighting functions i.e. orchestration of gene gating, replication fork dynamics and DNA damage repair. Second, we will address pharmacological targeting of PHF6 and its interactors as this has been so far underexplored as entry point for synthetic lethality in pediatric solid tumors such as neuroblastoma.