Identifying vulnerabilities of chromosomal instability: equal sharing is caring

Abstract

To maintain tissue homeostasis, cells need to duplicate and equally divide their genetic information over two new daughter cells. This process is tightly controlled, and for good reason: faulty cell division brings the risk of cell death. In contrast to healthy cells, cancer cells tend to make mistakes during cell division. Often, chromosomes fail to segregate correctly, leading to daughter cells with abnormal chromosome counts. This ongoing process of segregation errors is referred to as chromosomal instability (CIN). CIN has been linked to poor prognosis and increased therapy resistance. However, since this is a cancer cell specific trait, CIN could be a potential target to specifically attack genetically unstable cancer cells.

In this thesis, we took multiple approaches to identify vulnerabilities of chromosomal unstable cancer cells. For this, we utilized a genetic screening platform in human haploid HAP1 cells, and induced CIN by different mechanisms; spindle assembly checkpoint (SAC)-deficiency, replication stress or by chromosome condensation defects. The core aim of the project was to find genes that are important for the survival of CIN cells in general. Therefore, we focused on the genes that hit in all three conditions. Interestingly, we identified 17 genes, under which several kinetochore proteins, ER proteins, ubiquitin ligases, a phosphatase and RNAseH2. These genes could represent genes that are generally important for cells with an unbalanced genome and might encompass interesting targets for the clinic. Unfortunately, the level of synthetic lethality of the overlapping hits was mild. Therefore, we exploited the hits per screen separately. Because we found more optimal targets in each individual unstable background than in all backgrounds combined, we believe that cancer patients will benefit most from identifying the underlying cause of the genetic instability in their tumor, in order to target the tumors vulnerability specifically.