Western Sydney Local Health District (WSLHD) is proudly highlighting a groundbreaking discovery in cancer research that could significantly improve cancer treatments and increase cure rates.
Westmead Health Precinct scientists from WSLHD and Children’s Medical Research Institute (CMRI) have solved a major mystery: why cells die in different ways following radiotherapy.
The findings were published in Nature Cell Biology by first author Dr Radoslaw Szmyd of CMRI’s Genome Integrity Unit led by Professor Tony Cesare, with contributions from Western Sydney Local Health District Radiation Oncology Network’s associate professors Harriet Gee and Eric Hau.
Radiation therapy (also called radiotherapy) is a critically important type of cancer treatment.
Scientists have struggled for decades to understand why radiation therapy kills cells from the same tumour in different ways.
This is important because some forms of cell death are unnoticed by the immune system, while others trigger an immune response that kills other cancer cells.
Unleashing the patient’s immune system to kill cancer cells and clear tumours 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 Prof Cesare.
“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 recognise when overwhelming damage has occurred (e.g., from radiotherapy), and instruct a cancer cell how to die.”
“When DNA damaged by radiation therapy was repaired by a method called homologous recombination cancer cells died during the process of reproducing – a process called cell division or mitosis.”
“Unfortunately, death during cell division goes unnoticed by the immune system, so it won’t activate an immune response.”
“However, cells that dealt with the radiation-damaged DNA through other DNA repair methods survived the cell division process but did so by releasing byproducts of DNA repair into the cell.”
“These repair byproducts mimic a viral or bacterial infection, causing the cancer cell to die in a way that alerts the immune system. This is the response we aim to achieve.”
The research team demonstrated that blocking homologous recombination changed the way cancer cells died, triggering a strong immune response instead.
They also found that cancer cells with mutations in BRCA2—a gene critical for breast cancer and homologous recombination—did not die in mitosis following radiotherapy.
In addition to solving a major scientific puzzle, these discoveries will make it possible to use drugs that block homologous recombination to force cancer cells treated with radiotherapy to die in a manner that alerts the immune system to the existence of a cancer, (which the immune system had not previously noticed), signalling that the cancer needs to be destroyed.
Co-project lead, Associate Professor Harriet Gee, a radiation oncologist from the WSLHD Radiation Oncology Network, emphasised the clinical significance of these findings.
“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, focussed doses.”
This opens up new opportunities to enhance radiation efficacy through combination with other therapies, particularly immunotherapy, to increase cancer cures.
Prof Cesare credited these breakthroughs to live cell microscope technology, which enabled his team to observe irradiated cells for a week following radiation therapy.
“Live imaging showed us the full complexity of outcomes following radiation therapy, allowing us to tease out exactly why this occurred.”
Dr Szmyd dedicated six years to this “incredibly difficult nut to crack.”
Prof Cesare praised the team’s perseverance.
“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, Prof Hilda Pickett, Dr Chrisopher Nelson, and Dr Andrew Dhawan from the Neurological Institute at the Cleveland Clinic in the US and A/Prof Eric Hau from the Westmead Clinical School at the University of Sydney. Both A/Prof Gee and A/Prof Hau are staff specialists in Radiation Oncology in Western Sydney Local Health District.