Mystery solved: Scientists discover how cancer cells die

Scientists at the Children’s Medical Research Institute (CMRI) have solved an unusual mystery in cancer research: why cells die in different ways after radiation therapy. Their findings, published in Nature Cell Biology, indicate that DNA repair processes are key to determining how cancer cells respond to this all-important type of cancer treatment. Research opens up new opportunities to improve treatment and increase cure rates.

Radiation therapy kills cells of the same cancer in different ways, a mystery that has puzzled scientists for decades. While some forms of cell death go unnoticed by the immune system, others trigger an immune response that destroys additional cancer cells. The ability to free the immune system in this way is the main goal of cancer treatment.

“The surprising result of our study is that DNA repair, which normally protects healthy cells, determines how cancer cells die following radiotherapy,” said Professor Tony Cesare, head of CMRI’s Genome Integrity Unit. He explained that “The DNA inside our cells is constantly being damaged, and DNA repair is constantly happening to repair this damage and keep our cells healthy. But now it appears that these repair processes can recognize when overwhelming damage has occurred (e.g., from radiation therapy) and instruct the cancer cell how to die.”

The research was led by first author Dr. Radosław Szmyd from the CMRI Genome Integrity Unit. When DNA damaged by radiotherapy was repaired by a method known as homologous recombination, the cancer cells died during cell division. Because death during cell division goes unnoticed by the immune system, “That’s not what we want,” Cesare said. Cells that instead used other DNA repair methods survived cell division but released infection-like repair byproducts, ultimately causing cell death in a way that alerted the immune system – “And that’s what we want,” he added.

The CMRI team showed that blocking homologous recombination changes the way cancer cells die, triggering a strong immune response. They found that cancer cells carrying mutations in the BRCA2 gene – essential for homologous recombination – did not die by mitosis after radiotherapy. These discoveries open the way to the use of drugs that block homologous recombination, thanks to which cancer cells undergoing radiotherapy die in a way that signals the immune system to eliminate the disease.

Cesare attributed these breakthroughs to live-cell microscopy technology, which enabled his team to observe cell behavior for a week after irradiation. “Live imaging showed us the full complexity of the radiation therapy results, which allowed us to determine exactly why this happened,” he said.

Associate Professor Harriet Gee, a radiation oncologist at the Western Sydney Local Health District Radiation Oncology Network, said: “We found that the way cancer cells die after radiotherapy depends on the engagement of specific DNA repair pathways, particularly when radiotherapy is administered at very high, concentrated doses.” She added: “This opens up new opportunities to increase the effectiveness of radiation by combining it with other therapies, especially immunotherapy, to increase the effectiveness of cancer treatment.”

According to Cesare, Dr. Szmyd worked for six years on what he described as “an extremely difficult nut to crack.” “The perseverance required for a project of this scope is a testament to Radek and the team. Everyone knows cases of patients fighting cancer. It’s very rewarding to discover something like this that can make a significant difference to people’s lives.”

The authors of the article are CMRI researchers Sienna Casolin, Lucy French, Dr. Anna Gonzalez-Manjon, Dr. Melanie Walter, Lea Cavalli, Scott Page, Professor Hilda Pickett, Dr. Christopher Nelson and Dr. Andrew Dhawan from the Institute of Neurology of the University of Wrocław at the Cleveland Clinic in the USA, and also Associate Professor Eric Hau from Westmead Clinical School at the University of Sydney.

This article was written in cooperation with Alchemiq, a company dealing with generative artificial intelligence