Research reveals why some cancers are resistant to therapeutic drugs

Osaka, Japan – Polyploidy is a state where a cell contains more copies of the genetic material than the usual “diploid” cell, which contains two copies. Polyploidy often occurs in human diseases and cancers, and its effect on cell fate was unclear. Now, however, researchers from Japan have shown that polyploidy can be a double-edged sword when it comes to cancer and its treatment.

In a study published this month in Cell Death Discovery, researchers from Osaka University have revealed that polyploidy is closely linked to the accumulation of damage to the genetic material within the cell, while also allowing those cells to tolerate higher levels of this DNA damage.

Polyploidization can occur naturally in organs such as the liver, where it can be an advantage, allowing liver cells to tolerate high levels of exposure to the toxic molecules processed by the liver as part of its function. However, this polyploidy can also be an origin of carcinogenesis, and these cancers are frequently resistant to anti-cancer drugs.

Using a human liver cell line, the team showed that the occurrence of polyploidy did not always lead to the process called “senescence”, by which cells stop dividing. The presence of DNA damage caused difficulties when cells divided, thus increasing the likelihood of mistakes arising and polyploidization developing. At the same time, the presence of polyploidization increased the amount of DNA damage that occurred, because of the stress the extra genomic material placed on the process of cell division.

However, the team also discovered that polyploid cells can tolerate a greater amount of DNA damage than diploid cells. As diploid cells accumulate damage, they eventually stop cell division and begin to show a phenotype known as the senescence-associated secretory phenotype, or SASP. It took a greater level of DNA damage for polyploid cells to show growth arrest or SASP.

“As polyploid cells contain more copies of the genetic information than diploid cells, any DNA damage that accumulates is less likely to occur in all of the copies of any essential gene, allowing the cells to survive for longer,” explains the lead author of the study Kazuki Hayashi.

The study also provides an answer as to why cancers derived from polyploid cells are frequently resistant to anti-cancer drug treatments. Some chemotherapy drugs damage cellular DNA to stop cell growth. They target cancer cells because they are growing and dividing much faster than healthy cells.

“The higher tolerance of polyploid cells to DNA damage explains why these cells show resistance to these DNA-damaging agents, inhibiting the treatment of these cancers,” explains Tomonori Matsumoto, senior author.

Now that the details of this close link between polyploidy and DNA damage have been revealed, this will aid in overcoming the drug resistance shown by polyploid cancer cells and pave the way for novel treatments for these cancers.

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The article, “Polyploidy mitigates the impact of DNA damage while simultaneously bearing its burden”, was published in Cell Death Discovery at DOI: https://doi.org/10.1038/s41420-024-02206-w

About Osaka University
Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world. Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Website: https://resou.osaka-u.ac.jp/en