Researchers find out how shattered chromosomes make most cancers cells greater aggressive

Overview

• Post By : Kumar Jeetendra


• Source: University of California - San Diego


• Date: 27 Dec,2020

Cancer is one of the world’s biggest health afflictions because, unlike some diseases, it’s a moving target, constantly evolving to evade and resist treatment.

In a paper published in the December 23, 2020 online dilemma of Nature, researchers at 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 the way the phenomenon called”chromothripsis” divides chromosomes, which then reassemble in ways that ultimately promote cancer cell growth.

Chromothripsis is a catastrophic mutational event in a cell’s history which involves massive rearrangement of its genome, rather than a slow purchase of rearrangements and mutations over time. Genomic rearrangement is a key characteristic of many cancers, allowing mutated cells to grow or grow faster, unaffected by anti-cancer therapies.

“These rearrangements can occur in a single step,” said first author Ofer Shoshani, PhD, a postdoctoral fellow in the laboratory of the paper’s co-senior author Don Cleveland, PhD, professor of medicine, neurosciences and cellular and molecular medicine at UC San Diego School of Medicine.

“Throughout chromothripsis, a chromosome in a cell is shattered into several pieces, hundreds in some cases, followed by reassembly in a shuffled order. Some pieces get lost while others persist as extra-chromosomal DNA (ecDNA). Some of these ecDNA components promote cancer cell growth and form minute-sized chromosomes called’double minutes.'”

Research published last year by scientists at the UC San Diego branch of the Ludwig Institute for Cancer Research found that around half of all cancer cells in various kinds of cancers include ecDNA carrying cancer-promoting genes.

In the latest study, Cleveland, Shoshani and colleagues used direct visualization of chromosome structure to identify the steps in gene amplification and the mechanism inherent resistance to methotrexate, among the first chemotherapy drugs and still widely used.

In collaboration with co-senior writer Peter J. Campbell, PhD, head of cancer, aging and somatic mutation at Wellcome Sanger Institute in the United Kingdom, the group sequenced the whole genomes of cells creating drug resistance, revealing that chromosome shattering jump-starts formation of ecDNA-carrying genes which confer anti-cancer therapy resistance.

The scientists identified how chromothripsis compels ecDNA formation after gene amplification inside a chromosome.

Said Cleveland:”Our identifications of repetitive DNA shattering as a driver of anti-cancer drug resistance and of DNA repair pathways necessary for reassembling the shattered chromosomal bits has allowed rational design of combination drug therapies to prevent development of drug resistance in cancer patients, thereby improving their results.”

The findings address one of the so-called nine Grand Challenges for cancer treatment development, a joint venture between the National Cancer Institute in the United States and Cancer Research UK, the world’s largest independent cancer research and awareness charity.