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All living things evolve over time, and cancer cells are no exception – subject to the two overarching mechanisms described by Charles Darwin: chance mutation and natural selection.
In new research, Carlo Maley and his colleagues describe compulsive evolution and dramatic genetic diversity in cells belonging to one of the most treatment-resistant and lethal forms of blood cancer: acute myeloid leukemia (AML). The authors suggest the research may point to new models in both the diagnosis and treatment of aggressive cancers, like AML.
Maley is a researcher at Arizona State University’s Biodesign Institute and an assistant professor in ASU’s School of Life Sciences. His work focuses on applying principles of evolutionary biology and ecology to the study of cancer.
The group’s findings appear in this week’s issue of the journal Science Translational Medicine.
The cells, they are a changin’
A tumor is a laboratory for evolutionary processes in which nature experiments with an immense collection of variants. Mutations that improve a cell’s odds of survival are “selected for,” while non-adaptive cells are weeded out in the evolutionary lottery.
Genetic diversity therefore provides cancer cells with a library of possibilities, with some mutations conferring heightened resistance to attack by the body’s immune system and others helping malignant cells foil treatments like chemotherapy.
The diagnosis of cancer is often accomplished by examining a tumor sample containing many billions of cells. These are subjected to so-called next generation sequencing, a technique that sifts the vast genetic composite, ferreting out sequence variants (or alleles). The process then evaluates the frequency of these alleles, using the results to chart disease progression and assess the effectiveness of treatment.
According to Maley, such methods may obscure the true degree of genetic diversity, as well as the manner in which mutations arise.
“One issue here is that if a mutation occurs in less than 20 percent of the cells, it’s hard to detect by modern methods,” Maley said.
For example, because individual cells in the tumor probably carry unique mutations, they would be virtually impossible to observe with standard sequencing methods.
A further issue is that tracking mutations through bulk analysis of cells is typically based on certain assumptions as to how mutations arise and what their frequencies mean.
A new window
The current study attempts to provide a more accurate picture of what is taking place at the genetic level when an AML patient has a relapse or metastasis of the disease. Rather than carry out conventional bulk analysis of cells, the research group examined individual cells, screening them for the presence of two critical gene mutations common in AML, known as FLT3 and NPM1.
The results significantly alter existing assumptions of cancer progression, indicating much greater genetic diversity in AML than previously assumed. The process of convergent evolution, in which separate lineages develop similar features, appears to account for some of the observed diversity. The researchers found evidence that the exact same mutation was occurring multiple times within the same patient.
Curbing cancer’s lethality
Given AML’s near-limitless capacity for creating novel variants, what can clinicians do to halt the disease’s pitiless advance?
According to Maley, one hopeful approach would be to use cancer’s evolveability to advantage, rather than attempt to fight it head on: “Can we put pressures on the tumor that select for a behavior that we want – a manageable cancer that doesn't kill us?”
This new paradigm draws on a branch of ecology known as life history theory. The idea is to carefully study the environmental factors that may lead organisms to favor either a fast reproducing or slow reproducing strategy to maximize their survivability.
“This approach would say ‘let’s keep tumors as stable as possible and keep their resources limited.’ If we are able to keep the tumor cells contained and let them fight it out, we would expect to see more competitively fit cells that are growing very slowly,” Maley said.
While the current single-cell analysis evaluated just two mutations in AML, the results demonstrated the staggering evoleability of this form of cancer.
Eventually, researchers like Maley would like to examine whole genomes in single cells but currently many technical hurdles exist. Nevertheless, evolutionary approaches to cancer are already suggesting a broad rethinking of this complex of diseases.
A longer version of this story is available on the ASU Biodesign site.