Study uncovers how cancer cells thrive with extra chromosomes microbiologystudy

Cancer cells have special adaptation mechanisms that allow them to proliferate despite changes in their genetic makeup. Researchers at RPTU University Kaiserslautern-Landau, Southwest Germany, have now helped to elucidate the molecular mechanisms involved. The findings could be an important milestone in the development of targeted cancer therapies.

The nucleus of every human cell contains chromosomes—23 pairs, to be exact. These carry our genetic material, known as the genome, and are composed of deoxyribonucleic acid (DNA) and proteins. DNA stores genetic information and is therefore central to the inheritance of traits.

Chromosomal changes can have serious consequences for the affected cells, including the development of cancer. How such changes can occur and what exactly the consequences are, is the focus of the research of Professor Zuzana Storchová, Head of the Molecular Genetics Department at RPTU.

She is doing this with the help of a team of researchers, including Ph.D. student Jan-Eric Bökenkamp, who explains, “We study the genetic characteristics of cancer cells and their molecular properties both experimentally and through computational analysis.”

Around 90% of tumors consist of aneuploid cells

In a recent article published in The EMBO Journal, the researchers took a closer look at a common genetic feature of cancer cells, known as aneuploidy.

“When a cell is aneuploid, it has an altered set of chromosomes,” explains Storchová. A well-known example of aneuploidy is found in people with Down-Syndrome, who have an extra copy of chromosome 21, known as trisomy 21. “What is less well known is that about 90 percent of tumors in cancer patients also consist of aneuploid cells, and in most cases more than one chromosome is affected at the same time.”

Since aneuploidy slows down the growth of healthy cells and often leads to cell death, a key question in cancer research is: why and how are cancer cells with this genetic burden able not only to survive but also to proliferate?

In the laboratory, Storchová and her team of researchers therefore genetically engineered cells to carry an extra copy of a chromosome, i.e. to be aneuploid. Bökenkamp says, “We allowed the stressed cells to proliferate over a longer period of time and found that they grew significantly better after several weeks.”

The researchers carried out many different experiments to understand the molecular mechanisms that enable aneuploid cells to adapt in this way. For this, they used modern methods of biotechnology and bioinformatics, such as next-generation DNA sequencing and mass spectrometry.

First laboratory to study the adaptation of cancer cells to extra chromosomes

Storchová emphasizes the special nature of their research: “Our study is unique in that we are the first laboratory to have developed and analyzed a model system to study the adaptation of human cancer cells to the persistent presence of certain extra chromosomes.”

The researchers also analyzed public observational data from thousands of tumors with aneuploid cells from cancer patients in US-based databases “to compare them with the experimental data from our aneuploid model cells and to support the clinical relevance of our findings,” Bökenkamp adds.

Three ways how cancer cells adapt to the presence of extra chromosomes

In summary, the researchers have identified three ways in which cancer cells adapt to the presence of extra chromosomes: First, they increase the stability of their genome by increasing the number of DNA replication and DNA repair factors and reduce the degradation of gene products. Second, they increase the activity of the cell growth and division factor FOXM1. Thirdly, they lose certain parts of the extra DNA that encode tumor suppressor genes, while retaining the parts that encode growth-promoting genes.

The researchers conclude that these findings could be used to develop new therapeutic approaches and drugs. Approaches that specifically inhibit the very molecular processes that enable cancer cells to grow and multiply despite extensive genomic alterations. FOXM1 is an especially promising target, as its potential for cancer drugs has been the subject of research for several years.

Provided by
Rheinland-Pfälzische Technische Universität Kaiserslautern-Landau