Researchers believe that smaller cells may be more vulnerable to DNA-damaging agents such as chemotherapy combined with targeted drugs, while larger cancer cells may respond better to immunotherapy.
The study was published in the journal Science Advances.
It combined innovative high-performance image analysis with the study of DNA and proteins to study the size control of millions of skin cancer cells.
Skin cancer melanoma is caused by two different genetic mutations – 60 percent of cases are caused by a BRAF gene mutation, while 20-30 percent of cases are caused by an NRAS mutation.
The researchers decided to study the differences in size and shape of skin cancer cells with the two mutations, using mathematical algorithms to analyze vast amounts of DNA and protein.
The main difference was the size of the cells. BRAF mutant cancer cells were very small, while NRAS mutant cancer cells were much larger. Drug-resistant NRAS cells were even larger.
Smaller cells seem to be able to tolerate more DNA damage because they have a high concentration of proteins that repair DNA – such as PARP, BRCA1 or ATM1 proteins.
ICR researchers believe this could make them more vulnerable to drugs such as PARP inhibitors – drugs that block the proteins responsible for repairing DNA damage – especially when combined with DNA-damaging agents such as chemotherapy.
In contrast, the larger NRAS mutant cancer cells contained damage to their DNA instead of repairing it, accumulated mutations, and grew larger. These larger cells were less dependent on the DNA repair machinery, so using chemotherapy and PARP inhibitors against them might not be as effective.
The researchers believe that larger cells may respond better to immunotherapy – because their higher number of mutations could make them appear more foreign to the body. They are already investigating this theory with further research.
Researchers believe that BRAF and NRAS mutations may cause differences in cell size by regulating the levels of the CCND1 protein – which is involved in cell division, growth and maintaining the cytoskeleton – and its interactions with other proteins.
The study focused on skin cancer cells, but researchers suspect that this ability to change size and its effect on treatment response is common to many types of cancer. They have already identified similar mechanisms in breast cancer and are now investigating whether the findings could apply to head and neck cancers.
The discovery provides new information about how cancer cell size affects the overall disease, allowing better predictions of how people with cancer will respond to different treatments simply by analyzing cell size.
Existing drugs could even be used to force cancer cells to a desired size before treatments such as immunotherapy or radiation therapy, which could improve their effectiveness.
Director of studies, professor Chris Bakalprofessor of cancer morphodynamics at The Institute of Cancer Research, London, said: “We think of cancer as uncontrollable and unpredictable, but we used image analysis and proteomics to show for the first time that certain genetic and protein changes lead cancer cells to shrink or grow to improve their ability to repair or prevent DNA damage , which in turn can make them resistant to certain treatments.
“We believe that our research has real diagnostic potential. By looking at cell size, pathologists can predict whether a drug will work or whether the cells are resistant. In the future, it may even be possible to use artificial intelligence to guide the pathologist. , making a quick assessment of cell size and thus the treatments most likely to work.”
“We also hope that our discovery will lead to new treatment strategies – for example, creating drugs for proteins that regulate cell size.”
Professor Kristian HelinChief Executive of the Institute of Cancer Research, London, said: “This fascinating fundamental research provides a correlation between genetic changes and cell size in skin cancer cells. It opens up the possibility of using genetic changes and cell size as biomarkers for skin behaviour. It is particularly exciting that cell size may also be an important biomarker for how others eat, such as breast or head and neck cancers, respond to treatments.”
Source: The Nordic Page