Scientists at the Institute of Cancer Research (ICR), London, combined biochemical profiling technologies with mathematical analyses and found that cancer cells can shrink or super size to survive drug treatment or other obstacles in their environment. The findings provide new insight into how the size of cancer cells affects the overall disease.
Their study is published in Science Advances in an article titled, “Characterization of proteome-size scaling by integrative omics reveals mechanisms of proliferation control in cancer.”
The researchers set out to investigate the differences in size and shape of skin cancer cells, which are driven by two different genetic mutations, by using mathematical algorithms to analyze huge amounts of data on DNA and proteins.
The team observed a significant difference in size. BRAF-mutant cancer cells were very small whereas NRAS-mutant cancer cells were much bigger. Drug-resistant NRAS cells were even bigger.
Smaller cells appeared to be able to tolerate higher levels of DNA damage, as they are very concentrated with proteins that repair DNA—like PARP, BRCA1, or ATM1 proteins.
In contrast, the larger NRAS-mutant cancer cells contained damage to their DNA instead of repairing it, accumulating mutations and enlarging. These larger cells were not as reliant on DNA repair machinery, so using chemotherapy and PARP inhibitors against them might not be as effective.
The researchers believe BRAF and NRAS mutations may be driving the differences in cell size by regulating levels of a protein known as CCND1—which is involved in cell division, growth, and maintaining the cytoskeleton—and its interactions with other proteins.
Although the team focused on skin cancer cells, they suspect that this size-shifting ability and its impact on treatment response is common to multiple cancer types. They have identified similar mechanisms in breast cancer and are now investigating whether the findings could apply to head and neck cancers.
“We think of cancer as out of control and unpredictable, but we used image analysis and proteomics to show for the first time that certain genetic and protein changes lead to a controlled change in the size of cancer cells,” said study leader Chris Bakal, PhD, professor of cancer morphodynamics at ICR. “Cancer cells can shrink or grow to enhance their ability to repair or contain DNA damage, and that in turn can make them resistant to certain treatments.
“We think our research has real diagnostic potential. By looking at cell size, pathologists could predict whether a drug will work, or if the cells will be resistant. In the future, it might even be possible to use AI to help guide the pathologist, by making a rapid assessment about the size of cells and so the treatments that are most likely to work.
“We also hope our discovery will lead to new treatment strategies—for example creating drugs to target the proteins that regulate cell size.”
“This intriguing, fundamental study provides a correlation between genetic alterations in skin cancer cells and cell size,” explained Kristian Helin, PHD, chief executive of ICR. “It opens the potential of using genetic alterations and cell size as biomarkers for how skin cancer will respond to treatments. It’s particularly exciting that cell size could also be an important biomarker for how other cancers, such as breast or head and neck cancers, respond to treatments.”
