Cancer is one of the biggest health problems in the world because, unlike some diseases, it is a moving target that is constantly evolving to avoid treatment and resist it.
In a paper published in the online edition of the journal. December 23, 2020
Nature, researchers from 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 UK, describe how a phenomenon known as ‘chromotrips’ breaks chromosomes, which are then reassembled in ways that they ultimately promote the growth of cancer cells.
Chromotripsy is a catastrophic mutation event in the history of a cell that involves a massive rearrangement of its genome, as opposed to the gradual accumulation of rearrangements and mutations over time. Genomic rearrangement is a key feature of many cancers, allowing mutated cells to grow or grow faster without being affected by cancer therapies.
“These rearrangements can happen in one step,” said the first author, Dr. Ofer Shoshani, postdoctoral fellow in the laboratory of the co-senior author, Dr. Don Cleveland, Professor of Medicine, Neuroscience and Cellular and Molecular Medicine at UC San Medical School Diego.
“During chromotripsy, the chromosome in a cell breaks down into many parts, hundreds in some cases, followed by reassembly in a mixed order. Some parts are lost, while others survive as extrachromosomal DNA (ecDNA). Some of these ecDNA elements promote the growth of cancer cells and form “double minute” size chromosomes. “
A study published last year by scientists from the UC San Diego branch of the Ludwig Institute for Cancer Research found that as many as half of all cancer cells in many types of cancer contain ecDNA that carries genes that promote cancer.
In a recent study, Cleveland, Shoshani, and colleagues used direct visualization of chromosome structure to identify steps in gene amplification and the mechanism underlying resistance to methotrexate, one of the earliest chemotherapy drugs still widely used.
In collaboration with co-senior author dr. Peter J. Campbell, head of cancer, aging and somatic mutations at the Wellcome Sanger Institute in the UK, team sequenced whole genomes of drug-developing cells, discovering that chromosomal growth begins the formation of ecDNA-carrying genes that resist cancer therapy.
Scientists have also identified how chromotripsis triggers ecDNA production after gene amplification within chromosomes.
“Chromotrips converts intra-chromosomal (internal) amplifications into extrachromosomal (external) amplifications, and this enhanced ecDNA can then be reintegrated into chromosomal sites in response to DNA damage by chemotherapy or radiotherapy,” Shoshani said. “The new work emphasizes the role of chromotripsy in all critical phases of the life cycle of DNA-enhanced cancer cells, explaining how cancer cells can become more aggressive or drug-resistant.”
Cleveland said: “Our identifications of repeated DNA fragmentation as a driver of cancer drug resistance and DNA repair pathways necessary to reassemble broken chromosomal portions have enabled the rational design of combination drug therapies to prevent the development of drug resistance in cancer patients. improving their outcome. ”
The findings relate to one of the so-called nine major challenges for the development of cancer therapy, a joint partnership between the National Cancer Institute in the United States and Cancer Research UK, the world’s largest independent cancer research and awareness-raising organization.
Co-authors are: Ofer Shoshani, Peter Ly, Yael Nechemia-Arbely, Dong Hyun Kim, Rongxin Fang, Miao Yu, Julia SZ Li, Guillaume A. Castillon, Ying Sun, Mark H. Ellisman and Bing Ren, all at UC San Diego; Simon F. Brunner, Wellcome Sanger Institute; and Rona Yaeger, Memorial Sloan Kettering Institute of Cancer, NY.
Funding for this research was partly funded by the National Institutes of Health (grants R35 GM122476 and K99 CA218871), the Welcome Fund, the Swiss National Science Foundation, the Ludwig Institute for Cancer Research, the Memorial Sloan Kettering Cancer Center, the National Institute of General Medical Sciences (P41GM103412, R24GM137200) and award for top instruments.