Scientists at Children’s Medical Research Institute (CMRI) have solved a remarkable puzzle in cancer research: why cells die in different ways following radiotherapy. Their findings, published in Nature Cell Biology, point to DNA repair processes as the key to determining how cancer cells respond to this critically important type of cancer treatment. The research opens up new opportunities to improve treatment and increase cure rates.
Radiation therapy kills cells from the same tumor 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 unleash the immune system in this manner is a major goal of cancer treatment.
“The surprising result of our research is that DNA repair, which normally protects healthy cells, determines how cancer cells die following radiotherapy,” said Professor Tony Cesare, who leads CMRI’s Genome Integrity Unit. He explained that “The DNA inside our cells is constantly experiencing damage, and DNA repair is happening all the time to fix that damage and keep our cells healthy. Now, however, it seems these repair processes can recognize when overwhelming damage has occurred (e.g., from radiotherapy), and instruct a cancer cell how to die.”
The study was spearheaded by first author Dr. Radoslaw Szmyd of CMRI’s Genome Integrity Unit. When DNA damaged by radiation therapy was repaired by a method known as homologous recombination, cancer cells died during cell division. Because death during cell division goes unnoticed by the immune system, “This is not what we want,” said Cesare. Cells that used other DNA repair methods instead survived cell division but released repair byproducts that resembled an infection, ultimately causing the cell to die in a way that alerts the immune system—“Which is what we do want,” he added.
The CMRI team showed that blocking homologous recombination changed how cancer cells died, prompting a strong immune response. They found that cancer cells carrying mutations in the BRCA2 gene—vital for homologous recombination—did not die in mitosis following radiotherapy. These discoveries pave the way for using drugs that block homologous recombination so that cancer cells treated with radiotherapy die in a way that signals the immune system to eliminate the disease.
Cesare credited these breakthroughs to live cell microscope technology that allowed his team to observe cell behavior for a week after radiation. “Live imaging showed us the full complexity of outcomes following radiation therapy, allowing us to tease out exactly why this occurred,” he said.
Associate Professor Harriet Gee, a radiation oncologist from the Western Sydney Local Health District Radiation Oncology Network, said, “We found that the manner in which tumour cells die after radiotherapy depends on the engagement of specific DNA repair pathways, particularly when radiation is given at very high, focused doses.” She added, “This opens up new opportunities to enhance radiation efficacy through combination with other therapies, particularly immunotherapy, to increase cancer cures.”
According to Cesare, Dr. Szmyd worked for six years on what he described as an “incredibly difficult nut to crack.” “The perseverance required for a project of this scope is a testament to Radek and the team. Everyone is aware of patients battling cancer. Discovering something like this that has the potential to make a big difference to people’s lives is very rewarding.”
Authors on the paper include 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 Neurological Institute at the Cleveland Clinic in the US, as well as Associate Professor Eric Hau from the Westmead Clinical School at the University of Sydney.
This article was written in collaboration with generative AI company Alchemiq