Cancer is one of the biggest health problems in the world because, unlike some diseases, it is a moving target, constantly changing to avoid and withstand treatment.
In a paper published in the online journal 23 December 2020 of Nature, researchers at the University of California San Diego School of Medicine and the UC San Diego branch of the Ludwig Institute for Cancer Research, with colleagues in New York and the United Kingdom, describe how a phenomenon known as “ chromothripsis ”breaks down chromosomes, which are then reassembled in ways that eventually stimulate the growth of cancer cells.
Chromothripsis is a catastrophic mutational event in cell history that involves a major rearrangement of its genome, as opposed to a gradual remodeling and mutations over time. Genomic rearrangement is a key feature of many cancers, allowing mutated cells to grow or grow faster, unaffected by anti-cancer therapies.
“These changes can happen in one step,” said first author Ofer Shoshani, PhD, a postdoctoral fellow in the paper’s co-senior laboratory author Don Cleveland, PhD, professor of medicine, neuroscience and cell and molecular medicine at UC San Diego School of Medicine.
“During chromothripsis, a chromosome in a cell is broken down into many pieces, hundreds in some cases, and then reassembled in a moving sequence. Some pieces go missing and others continues as chromosomal extrinsic DNA (ecDNA) .Some of these ecDNA elements stimulate. cancer cell growth and the formation of minute-sized chromosomes known as ‘double minutes.’ “
A study published last year by scientists at the UC San Diego branch of the Ludwig Institute for Cancer Research found that ecDNA in up to half of cancer cells in many cancers carries cancer-inducing genes.
In the latest study, Cleveland, Shoshani and colleagues used a direct view of chromosome structure to identify the steps in gene proliferation and the underlying mechanism against methotrexate, one of the earliest and most widely used chemotherapy drugs. is still widely used.
In collaboration with lead author Peter J. Campbell, PhD, head of cancer, age and somatic mutations at the Wellcome Sanger Institute in the UK, the team developed a series of whole cell genomes developing drug resistance, revealing that a chromosome jump disrupts the onset jump of ecDNA-carrying genes that provide cancer resistance.
The scientists also identified how chromothripsis directs ecDNA formation after gene proliferation within a chromosome.
“Chromothripsis converts intra-chromosomal (internal) enlargements into chromosomal (externally) extensions and that expanded ecDNA can re-enter chromosomal spaces in response to DNA damage from chemotherapy or radiotherapy, “Shoshani said. “The new work clarifies the role of chromothripsis at all critical stages in an extended DNA life cycle in cancer cells, explaining how cancer cells can be more aggressive or drug-resistant.”
Cleveland said: “Our recognition of repeatable DNA fragmentation as a driver of anti-cancer drugs and DNA repair pathways necessary for the replacement of broken chromosomal fragments has allowed a reasonable design of combination drug therapies to prevent the development of drug resistance in cancer patients, therefore. improving the outcome. “
The findings address one of the nine Big Challenges known as the development of cancer treatment, a partnership between the National Cancer Institute in the United States and Cancer Research UK, the largest independent cancer research and awareness charity in the world.
Source:
University of California – San Diego