Image above: An illustration showing myeloma cells creating antibodies. The researchers studied the type of cancer known as multiple myeloma. Credit: Lydia Kibiuk / National Cancer Institute
Chemotherapy-resistant cancer cells could be returning to a more primitive form of single-cellular life, accessing an ancient ‘toolkit’ of behaviours that allows them to adapt, evolve and survive under stressful conditions, new research suggests.
Robert Austin (Princeton University), an advisor to CIFAR’s new Molecular Architecture of Life program, and lead author Amy Wu, who is now a postdoctoral fellow at the National Institute of Standards and Technology, developed a device to produce chemo resistance in cancer cells and then sequenced their RNA – the molecules that code for proteins, regulate cell behaviour and speed up chemical reactions.
To learn more about how the resistance emerged, they searched for “hot genes” with unusually high numbers of mutations relative to their lengths, as well as “cold genes” that weren’t mutated at all, but were being turned “on” or “off” at unusually high rates compared to their non-resistant equivalents. Searching for mutations in cancer genes is not new, but researchers were also curious if other genes without mutations might be playing a role in a way not yet fully understood.
The inspiration came from ideas originally suggested by Paul Davies at Arizona State and Charlie Lineweaver at Australian National University, “There’s a hypothesis that cancer has a survival toolkit,” says Wu. “And when they are in a harsh environment, such as chemotherapy, they try to open it up.” Wu explains that there have been previous studies that show bacteria can display such behaviour, repairing DNA and modifying its reproduction in response to stress.
The researchers found that, on an evolutionary time scale, both the hot and cold genes were as ancient as humanity’s origins in bacteria, suggesting that these older genes might be specifically targeted by cancer to adapt to the stress of chemotherapy. As a result, the team wonders if researchers have missed part of the story by focusing so heavily on mutations.
“We’ve sort of flipped the sign of where we think cancer chemotherapy should be moving,” Austin says. “A lot of the chemotherapy is going after genes that are mutated, but to my mind that means that they’re probably not that important. The ones that are never mutated might be the most important genes of them all.”
This unusual perspective on the role of non-mutated genes in cancer is a break from conventional studies that comes from looking with fresh eyes. Austin and Wu’s combined research experience spans a range of disciplines, including physics, atmospheric sciences, electronics, and electrical engineering. “I think what’s important is that you need to bring in people from the outside who think differently and that look at things in a different way, because you can get stuck in a rut, right?” Austin says. “There’s a need for people who are not expert to go into an area, and look at things from a different perspective.”
The findings were published in Proceedings of the National Academy of Sciences.
This research was funded in part by the National Cancer Institute.