Chromosomal instability causes DNA damage and promotes invasion

Chromosomal instability (CIN) is a phenomenon characterised by rapid changes in the number and structure of chromosomes during cell division. It is very common in solid tumours and is linked to the aggressive spread of cancer, that is to say, metastasis. Given that metastasis causes 90% of cancer-related deaths, it Is vital to unravel the details of this process. Besides the well known role of CIN in facilitating genomic evolution of cancer cells (through the gain of oncogene-carrying chromosomes and loss of tumor-suppressor carrying chromosomes), CIN has been shown in recent years to promote cancer metastasis through three pathways that occur as a secondary effect: on the one hand, aneuploidy (or irregular number of chromosomes in a cell, which causes cellular stress), on the other hand, the formation of micronuclei (and the inflammatory process they trigger) and, finally, DNA damage. The laboratory led by Marco Milan at IRB Barcelona has been using Drosophila as model system to study the role of CIN in cancer and metastasis for many years. In previous studies the team explored the effects of aneuploidy on this process. In the present work in 2023, they describe the third axis of action, namely the influence of DNA damage on the invasiveness of cancer cells. CIN can trigger DNA damage in three ways. First, the irregular segregation of chromosomes can cause a break in the DNA chain. Second, the imbalance in the number of chromosomes disrupts the cellular machinery, resulting in cellular stress during DNA replication. Third, as the researchers describe in this work, aneuploidy also stimulates the JAK/STAT signaling pathway, which in turn activates caspases and causes DNA damage. When functioning properly, caspases drive DNA damage, leading the cell to collapse and disintegrate. However, the researchers have now detailed how lower levels of caspase activity promote DNA damage. This work presents evidence that the these three sources of DNA damage promote invasiveness.