Chromosomal instability is a hallmark of solid tumors such as carcinoma. Likewise, cellular senescence is a process strongly linked to cellular aging and its link with cancer is becoming increasingly clear. Scientists led by ICREA researcher Dr Marco MilÃ¡n from IRB Barcelona have revealed the link between chromosome instability and cell senescence.
Chromosomal instability and senescence are two characteristics common to most tumors, yet it was not known how one relates to the other. Our studies indicate that senescence could be one of the intermediary links between chromosome alterations and cancer. “
Dr Marco Milan, Head of the Development and Growth Control Laboratory, IRB Barcelona
“The behavior we observed in cells with chromosomal instability made us think that they could be senescent cells and indeed they were!” says Dr Jery Joy, first author of the article published in Development cell.
The study was conducted on the fly Drosophila, an animal model commonly used in biomedicine, and the mechanisms described may help understand the contribution of chromosomal instability and senescence to cancer, and facilitate the identification of possible therapeutic targets.
Reverse the effects of chromosome instability
Researchers from the Development and Growth Control laboratory have shown that, in epithelial tissue with high levels of chromosomal instability, cells with altered chromosome number balance break away from neighboring cells and enter senescence. Senescent cells are characterized by a permanently arrested cell cycle and the secretion of a large number of proteins. This abnormal secretion of proteins alters surrounding tissue, alerting the immune system and causing inflammation.
If senescent cells are not immediately eliminated by the body, they promote abnormal growth of surrounding tissues, leading to malignant tumors. “If we identify the mechanisms by which we can reduce the number of senescent cells, then we will be able to reduce the growth of these tumors,” says Dr Milan. âIn fact, this study shows that it is possible, at least in Drosophila“says Dr. Joy.
Cells with an imbalanced number of chromosomes accumulate a high number of aberrant mitochondria and, as a result, a high level of oxidative stress, which in turn activates the JNK signaling pathway, triggering entry into senescence. âWe have shown that reducing this high number of mitochondrial abnormalities, or regulating the oxidative stress they induce, is sufficient to decrease the number of senescent cells and the negative effects of chromosomal instability,â reiterates Dr. Joy.
These results open new avenues of research to find therapeutic targets and reduce the levels of senescence caused by chromosomal instability in solid tumors.
Extrapolation from fly to mammals
The vinegar fly, Drosophila melanogaster, is widely used in biomedicine. It is a valuable animal model in cancer research due to its short life cycle, the availability of a large number of genetic tools, and the presence of the same genes as in humans, but with a lower redundancy level.
In fact, experiments designed to dissect the causal relationship between cellular behavior or characteristics of human tumors, such as chromosomal instability and senescence, are more easily analyzed in this model organism.
Future laboratory work will continue to dissect the molecular mechanisms responsible for cellular behaviors found in solid tumors of epithelial origin produced by the simple induction of chromosomal instability. “The more we understand the biology of a tissue subject to chromosomal instability and the molecular mechanisms responsible for the cellular behaviors that emerge and give rise to malignant tumors, the better our chances of designing effective therapies and reducing the growth and malignancy of the cells. Human carcinomas are large, âconcludes Dr. Milan.
Biomedicine Research Institute
Joy, J., et al. (2021) Proteostasis failure and mitochondrial dysfunction lead to aneuploidy-induced senescence. National Library of Medicine. doi.org/10.1016/j.devcel.2021.06.009.