Cheat Code: Cracking Cancer's Evolution to Help Defeat It

Kat Arney, PhD


February 19, 2021

The soil-dwelling amoeba Dictyostelium discoideum may seem a world away from the cleanliness of a cancer ward, but these microscopic creatures can teach us much about a disease that still claims the lives of more than 600,000 Americans every year.

Dictyostelium usually exists in a solitary unicellular form, but when food supplies run low, up to 100,000 cells will come together to create a small "slug" that migrates in search of more amenable conditions. Once in a suitable spot, the slug transforms again to create a vertical stalk topped with a bud-shaped fruiting body. Finally, the bud bursts open, scattering microscopic spores that are each capable of germinating into a new amoeba.

Although this unusual life cycle ensures the survival of the population, it doesn't directly benefit every amoeba that joins the slug. Around 1 in 5 cells end up in the stalk and are thus destined to die, sacrificing themselves for the greater good of the colony. Yet, even in this simple society, there are "cheats" that break the rules. 

A Selfish Mutation

In 1982, Yale University biologist Leo Buss noticed that particular cells in a related Dictyostelium species were more likely to end up in the spore body than in the stalk — referred to as "somatic cell parasites" — giving them a much better chance of contributing to the next generation.

A quarter of a century later, researchers showed that the same selfish behavior also happened in Dictyostelium discoideum and was due to mutations in any one of more than 100 different genes. Genetic variations making it more likely for a cell to push to the top of the stalk also increased its chances of survival and continuing to multiply, thereby creating a new generation of cells that also carry the same selfish mutation.

The same principle at work in these cheating amoebas can be seen in the emergence of cancer within the tissues of the body. There is growing interest in the long-overlooked concept of cancer as a disease driven by cellular "cheats" — mutated cells that outcompete and proliferate faster than their well-behaved neighbors, eventually creating a tumor that grows and metastasizes throughout the body. This view frames cancer as the inevitable consequence of multicellularity.

Cancer is a deep biological phenomenon dating back millions of years, observable in almost all branches of the animal kingdom (with the notable exceptions of comb jellyfish and sponges). We find traces of tumors in long-dead fossils and ancient human remains all over the world. Wherever there are mutated cells within multicellular organisms, there we will find the capacity for cancer.

The Darwinian Principle of Cancer Growth

It is overly simplistic, however, to assume that mutations are the only things that matter when it comes to creating a cancer.

Recent work from researchers at the Wellcome Sanger Institute in Cambridge, England, has revealed that our bodies become a patchwork of mutation as we age. Our cells pick up all kinds of genetic changes as we go through life, some caused by the biological processes of life itself and others caused by external agents. Many of these alterations would be classified as "tumor drivers" if they were to be found in a cancer.

The extent of this damage is astounding. The Sanger Institute team found that up to half of the cells in the esophagus carry a mutation in the prominent cancer driver gene NOTCH by middle age, despite appearing entirely normal.

Although cancer is common in the population, with 1 in 2 people expected to develop the disease at some point, it's vanishingly rare on an individual level. Barring any underlying hereditary gene variations, each one of us may develop only one, or maybe two or three, primary tumors in an entire lifetime from amidst the trillions of individual cells and cell divisions within our bodies.

Clearly, the ability of cheating cells to develop into a cancer is not just dependent on their genetic makeup but on their environment too. The Darwinian principle of "survival of the fittest" is often mistakenly interpreted as meaning that the biggest, strongest, fastest, or smartest organisms on the block will survive and proliferate.

In fact, natural selection favors those that are the best fit for the environment in which they are living. In the context of cancer cells, this is the microenvironmental milieu of our tissues. The proliferative and migratory abilities of rebellious mutated cells depend not only on their genetic makeup but also on the advantage that these mutations give them in terms of their fitness within the local tissue environment.

Of note, this microenvironment changes as we age. Inflammation, physical changes resulting from the breakdown of collagen and other structural elements, the gradual buildup of mutations in healthy cells, and other processes all shift the molecular landscape within our tissues. Potentially cancerous mutations that might be at a disadvantage in young tissue become a boon in an aging, inflamed environment, providing a selective advantage that enables dangerous cells to prosper.

A Complex Disease Requires Equally Complex Treatments

As well as underpinning the development of tumors in normal tissue, evolutionary principles also lie at the heart of the challenge of treating advanced metastatic cancer. Over recent decades, there has been a move toward an increasingly genetically reductionist view of cancer, driven by the plummeting costs of high-throughput next-generation sequencing technology. This has reinforced a paradigm of ever more targeted therapies for cancer, based on the underlying molecular makeup of an individual patient's disease.

Yet for all the fanfare and high price tags, targeted therapies have not brought the game-changing gains in survival that the headlines might have promised. Immunotherapy does have huge potential, although the current range of checkpoint inhibitors doesn't work for all and in some cases may even make cancers worse.

Notwithstanding the success of Gleevec (imatinib) — the poster child for molecularly targeted therapies — most of the current generation of treatments bring survival in the order of single-digit years, months, or in some cases mere weeks for advanced metastatic disease. In all too many cases, no matter how successful the treatment initially seems to be, at some point the cancer comes back. At best, oncologists may be able to pursue a "whack-a-mole" strategy, following each failed line of therapy with another until the options run out.

The root cause of this failure is heterogeneity. Cancer cells are on a continual evolutionary journey of mutation and proliferation, creating a genetically diverse population with a range of selective advantages and disadvantages, depending on the selective pressures at work. Once a cancer has grown to a certain size, somewhere in this heterogeneous population will be cells with mutations rendering them resistant to any treatment that can be thrown at them. Even within a tumor the size of a grain of sugar, the seeds of resistance may already have been sown.

It's time to think smarter about how we approach cancer treatment, acknowledging the evolutionary power of cancer and using it to our advantage. Adaptive therapies, developed by pioneers such as Robert Gatenby and his colleagues at the Moffitt Cancer Center in Tampa, Florida, aim to steer the trajectory of cancer by balancing populations of drug-resistant and sensitive cells through careful monitoring and dosing. This approach has shown remarkable success in advanced prostate cancer and is now being tested in other tumor types.

However, adaptive therapies still aim to control cancer rather than eradicate it. To do that, we need to think about extinction strategies: regimens designed to apply specific selective pressures at the right time to cause the population of cancer cells to collapse, just as multiple different factors (shrinking habitat, disease, predation, and so on) drive animal populations to extinction in nature. Unfortunately, there is little interest in developing and trialing such strategies based on the drugs we already have, compared with the enthusiasm of the pharmaceutical industry for developing ever more costly therapeutics.

This isn't to say that there has been no progress. After more than a century of research, around half of all people with cancer in countries like the United States and United Kingdom will survive for 10 years or more, particularly if diagnosed in the early stages of disease. But armed with a deeper understanding of all three elements of cancer — cellular mutations, tissue ecology, and evolutionary pressures — we will get closer to catching all of cancer's "cellular cheats" before they can take hold and become resistant to treatment.

Kat Arney, PhD, is a science writer and broadcaster living near London, England. She is the author of Rebel Cell: Cancer, Evolution, and the New Science of Life's Oldest Betrayal (BenBella Books).

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