Unraveling the causes of aneuploidy tolerance in cancer

Aneuploidy tolerance in cancer cellsCells are the building blocks of the human body. An adult human body consists of around 60 trillion cells which arose from one fused egg- and sperm cell. Before a cell can divide, it needs to duplicate its entire set of chromosomes (also called genome) and subsequently evenly divide them over the daughter cells. Cancer cells often have a faulty cell division which can result in the development of cells with an abnormal number of chromosomes, a state called aneuploid. Healthy cells which are made aneuploid usually have a growth disadvantage whereas cancer cells are often aneuploid and yet are able to grow very fast. Cancer cells have thus found ways to tolerate aneuploidy. The goal of this thesis is to identify new aneuploidy tolerating mechanisms.To identify such aneuploidy tolerating mechanisms we have studied what distinguishes aneuploid cancers from cancer cells with normal numbers of chromosomes (euploid). Aneuploidy can for example lead to a disturbed protein metabolism in cells, which can cause protein aggregation. We have shown that some aneuploid cancer cells overexpress certain genes to counteract protein aggregation in order to tolerate aneuploidy. To identify genetic changes that lead to aneuploidy tolerance we performed a genetic transposon mutagenesis screen in mice. By comparing the location of the transposons in aneuploid- and euploid blood cancer cells we have found recurrent aneuploidy-specific mutations. These mutations are though to play a role in aneuploidy tolerance and could aid the development of new therapies for aneuploid cancers