Scientists have cracked the mystery of how some cancer cells that ought not to survive could actually take help from their ‘neighbours’ to succeed and form drug-resistant tumours instead.
Drug resistance is one of the world’s major crises of the 21st century. When a pathogen that causes an infection or disease becomes drug-resistant, drugs that could cure these conditions become less effective. Pathogens acquire this ability in the form of certain genetic mutations although some non-genetic factors are also in play.
When a cancer takes root in a person’s body, the cancer cells can also become drug-resistant in the same way. Simple logic dictates that when the person takes a drug to destroy these cells, the drug-resistant cells will proliferate while the non-resistant cells won’t. However, the genetic changes that conferred drug-resistance to the cells will also have undermined their overall ‘fitness’. When the person isn’t taking a drug to treat the cancer, the drug-resistant cells should thus have a harder time surviving than their non-resistant peers. They are said to suffer a ‘growth penalty’.
How the evolutionarily less-fit cells survive such conditions is a puzzle scientists have been trying to solve for years.
A complex ecosystem
In past studies, scientists have tried to understand drug resistance by separating the corresponding cells from a larger population, making copies of them in the lab, and investigating them further. The researchers behind the new study realised this approach removes an important bit of context that could affect the cells’ prospects: the influence of other cells in their surroundings, especially the ancestors from which they ‘deviated’ by accumulating genetic changes.
Jeff Maltas, a postdoctoral research fellow at Cleveland Clinic and the lead author of the study, said scientists have appreciated the idea of tumours as a complex ecological system. He said his team’s idea came from multiple disciplines plus previous reports of high mutation rates within a tumour that had changes in pH and oxygen levels, among other conditions.
In a study published in 2022, for example, some members of the same team of researchers and others showed that even in the absence of a drug, drug-resistant mutant cells undergo large changes in growth rate. The authors attributed this to the environment in which the cells existed.
A surprise in a model
Conventionally, mutated cells have a certain growth rate in the presence of a drug and a lower one in its absence. In the new study, the researchers built a mathematical model based on the idea that these growth rates depend on the presence of a drug and on the cells’ environment. When cultured alone, drug-resistant cells grew more slowly than the cells from which they were ‘descended’. But when these cells and their ancestors were cultured together, the former grew much faster.
The model also revealed that the more ancestral cells there are in the same culture, the drug-resistant daughter cells also proliferated faster — so much so that the growth penalty vanished. The resulting tumour would be resistant to the drugs to come.
The researchers also found that even when there is no drug, the interactions between the evolving drug-resistant cells in the tumour’s environment still promoted drug resistance. The implication is that drug-resistant cells could be present in larger numbers, perhaps more than a clinician or medical researcher might expect, even before treatment begins.
The authors wrote in their paper that their work “both complements and builds off of recent studies from a wide range of disciplines, ranging from theoretical population genetics and ecology to clinical trials across several biological kingdoms.”
The ancestral advantage
The researchers also proposed a mathematical framework to explain why drug resistance is common and validated it with experiments using lung cancer cells.
First, they engineered three drug-resistant mutations in lung cancer cells in the lab and grew them together with different amounts of drug-sensitive ancestor cells. Then they observed how the different abundances of mutations in the cells affected their growth rate.
Jeff Maltas, a postdoctoral research fellow at Cleveland Clinic and the lead author of the study, at work in the lab.
| Photo Credit:
Cleveland Clinic/Annie O’Neill
The mutations they picked to engineer are commonly seen in lung cancer patients. They found that all the drug-resistant cells grew slower than their ancestors when grown in isolation. But when grown with their ancestors, they built up faster. The researchers also grew two types of drug-resistant cells together without the ancestor, and their growth rate didn’t increase. That is, interactions between evolutionarily different cells didn’t provide any growth advantage. Only interactions with ancestral cells did.
The idea that a mutation’s frequency or relative abundance dictates how fit the cells that have it are is not new, but experts said the current study emphasises this idea in the context of cancer cells accumulating drug-resistant mutations.
Clue to a new treatment
“A key conclusion … is that the ecological environment can greatly impact the phenotype of the mutant being studied. Removing that mutant from the ecology leads to an incomplete scientific picture,” Maltas said.
Mohit Kumar Jolly, an associate professor of bioengineering at the Indian Institute of Science, Bengaluru, said, “Most, if not all, current therapies in the clinic do not consider the impact of these interactions, and this study reveals how considering this important dimension can help potentially design more effective therapies.”
The researchers also said their findings could be extendable to any evolving system, including viruses that mutate and bacteria that acquire resistance to antibiotics.
The study also indicated a potential new target for developing drugs to fight cancer and infectious diseases. “If this phenomenon is as general as we think,” Maltas said, “future treatments may be developed to disrupt the ecological interactions themselves, leading to higher cure rates.”
The study was conducted by scientists from Cleveland Clinic and Case Western Reserve University, Cleveland. The findings were published in the journal PRX Life in June 2024.
Joel P. Joseph is a freelance science journalist and researcher.
Published – September 11, 2024 05:30 am IST
