Chromosomal instability (CIN) is a defining characteristic of most human cancers. Mutation of CIN genes increases the probability that whole chromosomes or large fractions of chromosomes are gained or lost during cell division. It is very common in solid tumors and is linked to metastasis. Given that metastasis causes 90% of cancer-related deaths, researchers are seeking to unravel the details of this process. Now, scientists from IRB Barcelona’s Development and Growth Control Laboratory, ​​led by ICREA researcher Marco Milán, PhD, have revealed how DNA damage caused by chromosomal instability increases the invasiveness of cancer cells.

The research details how such instability activates a signaling pathway known as JAK/STAT and promotes caspase activity, which in turn causes DNA injury. This damage allows cells to escape from the primary tumor, thereby leading to metastasis.

Their findings are published in Current Biology in an article titled, “Chromosomal instability-induced cell invasion through caspase-driven DNA damage.”

“CIN, an increased rate of changes in chromosome structure and number, is observed in most sporadic human carcinomas with high metastatic activity,” wrote the researchers. “Here, we use a Drosophila epithelial model to show that DNA damage, as a result of the production of lagging chromosomes during mitosis and aneuploidy-induced replicative stress, contributes to CIN-induced invasiveness. We unravel a sub-lethal role of effector caspases in invasiveness by enhancing CIN-induced DNA damage and identify the JAK/STAT signaling pathway as an activator of apoptotic caspases through transcriptional induction of pro-apoptotic genes.”

“We have long considered caspases as agents that induce cell death in response to DNA damage. However, our findings indicate that they may also play a pro-invasive role by promoting DNA damage. This research broadens our understanding of cancer biology and paves the way to exploring new therapeutic approaches to tackle metastasis,” explained Milán.

The laboratory has been studying the role of chromosomal instability in cancer and metastasis for many years. In previous studies, published in 2018 and 2021, the team explored the effects of aneuploidy on this process. In the present work, they describe the third axis of action, the influence of DNA damage on the invasiveness of cancer cells.

The researchers show in this work that 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, thereby conferring cancer cells the capacity to metastasize.

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