New research led by the Garvan Institute of Medical Research reveals cancer cells have an innate randomness in their ability to respond to chemotherapy. The team showed that tumor cells from neuroblastoma can move between states of responding or not to chemotherapy.
The findings are published in Science Advances in an article titled, “Memory of stochastic single-cell apoptotic signaling promotes chemoresistance in neuroblastoma.”
“Gene expression noise is known to promote stochastic drug resistance through the elevated expression of individual genes in rare cancer cells,” wrote the researchers. “However, we now demonstrate that chemoresistant neuroblastoma cells emerge at a much higher frequency when the influence of noise is integrated across multiple components of an apoptotic signaling network. Using a JNK activity biosensor with longitudinal high-content and in vivo intravital imaging, we identify a population of stochastic, JNK-impaired, chemoresistant cells that exist because of noise within this signaling network.”
“We showed there is ‘noise’ in the process of cell death, which is what happens to cancer cells with chemotherapy treatment—and that this inherent noise, or randomness, in the system of gene expression is an important aspect of chemoresistance,” said associate professor David Croucher, PhD, head of the Network Biology Lab at Garvan.
About 15% of people with neuroblastoma don’t respond to chemotherapy treatment.
“Our findings suggest that genetics don’t account for everything; other layers of regulation and other mechanisms of tumor progression can also underpin drug response, so we need to consider them,” said Sharissa Latham, PhD, group leader at Garvan and co-lead author on the study.
The team showed that once neuroblastoma cells reach a state of resisting chemotherapy, they can’t go back, suggesting there is a small window where treatment could work on a tumor cell before it’s locked in.
“Combining chemotherapy with drugs that target this noise within tumors may have the best results as a first-line treatment after diagnosis before tumors lock into a state of resistance,” said Croucher. This flips on its head the typical protocol for clinical trials in cancer where a new treatment is given to patients who have exhausted all other treatment options.
The researchers used mathematical modeling to narrow down the “noise” signals in the pathways of cell death in neuroblastoma tumors. They then applied that to patient cell samples and found a marker for resistance, a set of proteins involved in the process of apoptosis.
“We wanted to figure out what underlies that randomness. What is it about those cells and can anything be manipulated to make them respond,” said Latham.
The researchers are looking forward to progressing the work to a clinical trial.