Therapeutic targeting of cytokinesis eradicates genomically silent childhood cancer

Li, Jing (2021): Therapeutic targeting of cytokinesis eradicates genomically silent childhood cancer. Dissertation, LMU München: Medizinische Fakultät

Abstract

One feature of cancer is chromosomal instability (CIN). Through moderate CIN, most cancer types acquire somatic copy number alterations during each cell division creating intra-tumor heterogeneity that enhances the overall ‘fitness’ of the cancer cell population. Yet, excessive CIN can lead to non-viable karyo-types. While CIN-induction in cancer types that are intrinsically genomically instable may have little therapeutic benefit, it may cause massive cell death in cancers with ‘silent’ or nearly diploid genomes, as for instance in many pediat-ric cancer types including Ewing sarcoma (EwS). To identify a candidate gene that could offer a large therapeutic window, the results presented in this thesis focused on protein regulator of cytokinesis 1 (PRC1), the most significantly overexpressed cytokinesis-related gene in EwS. PRC1 plays pivotal roles in orchestrating cytokinesis through its direct in-volvement in bundling of antiparallel microtubules (MTs) required for spindle midzone formation, recruitment of and interaction with other spindle midzone effectors and regulatory proteins. The results presented in this thesis show that EWSR1-FLI1 directly hijacks PRC1, which physiologically safeguards controlled cell division, through bind-ing to a proximal enhancer-like GGAA-microsatellite (mSat) thereby promoting tumor growth and poor clinical outcome. Moreover, high PRC1 expression creates a therapeutic vulnerability toward pharmacological PLK1 inhibition at clinically achievable dosages that can repress growth of even chemo-resistant EwS cells by triggering mitotic catastrophe.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 27. April 2021
• 1. Bericht­erstatter:in: Grünewald, Thomas