Understanding why some tumour cells become resistant to chemotherapy is a core challenge in cancer research, as chemotherapy is still a frontline treatment for most cancers.
The new research shows that tumour cells from neuroblastoma - cancer that develops in the body's 'fight or flight' sympathetic nervous system - can move between states of responding, or not, to chemotherapy.
"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," says Associate Professor David Croucher, 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 tumour progression can also underpin drug response, so we need to consider them," says Dr Sharissa Latham, 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 tumour cell before it's locked in.
"Combining chemotherapy with drugs that target this noise within tumours may have the best results as a first-line treatment after diagnosis, before tumours lock into a state of resistance," says Associate Professor 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 new study is published in the journal, Science Advances.
Noise in the tumour systemThe researchers used mathematical modelling to narrow down the 'noise' signals in the pathways of cell death in neuroblastoma tumours. They then applied that to patient cell samples, using cutting-edge imaging to look at single cells, en masse, to visually isolate the cells that didn’t respond to treatment.
The found a marker for resistance - a set of proteins involved in the process of cell death, known as 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," says Dr Latham.
The team identified certain classes of approved drugs that might be combined with chemotherapy to stabilise expression of the genes involved in cell death, or by changing the innate threshold that may tip a tumour cell into a resistant state.
The next step is to start progressing the work to clinical trial.
Hastings JF, Latham SL, Kamili A, Wheatley MS, Han JZR, Wong-Erasmus M, Phimmachanh M, Nobis M, Pantarelli C, Cadell AL, O'Donnell YEI, Leong KH, Lynn S, Geng FS, Cui L, Yan S, Achinger-Kawecka J, Stirzaker C, Norris MD, Haber M, Trahair TN, Speleman F, De Preter K, Cowley MJ, Bogdanovic O, Timpson P, Cox TR, Kolch W, Fletcher JI, Fey D, Croucher DR.
Memory of stochastic single-cell apoptotic signaling promotes chemoresistance in neuroblastoma.
Sci Adv. 2023 Mar 3;9(9):eabp8314. doi: 10.1126/sciadv.abp8314