by Catherine Gutierrez
figures by Aparna Nathan

Forty-nine years ago, President Richard Nixon launched a “War on Cancer”. That war has not ended—it rages on today, with cancer right behind heart disease as the leading cause of death in the United States. Nearly 1.8 million new cases of cancer are expected in 2020 in the U.S. alone, and rising rates of cancer risk factors such as heart disease and obesity are likely to increase this number in upcoming years.

Luckily for us, we are also learning a lot more about how cancer works. It is not a stable disease, but rather one that is highly adaptable and constantly changing in response to its environment. Thanks to new technologies, we now have ways to tag and track cancer cells to see how they change over time. DNA barcoding, for example, is one approach by which short strips of synthetic DNA sequences are integrated into natural DNA to label individual cancer cells. Similar to the black and white stripes on commercial products that help us identify merchandise, DNA barcodes can help us distinguish certain cells from others. Another approach is to use glowing molecules to ‘paint’ cells and follow the paths of these glowing cells visually. Using these new technologies, we can trace millions of cancer cells and discover the different routes that each cell can take to successfully grow, spread, and develop resistance to treatment. If we can better understand how cancer evolves, we can anticipate its response to therapy and build an arsenal of more precise, targeted therapies.

Cancer – a disease of mutations

Cancer happens when cells in our body grow out of control, crowding out healthy cells. These rapidly growing cancer cells deprive neighboring healthy ones of nutrients and even release molecules that can inhibit the growth, migration and function of surrounding, noncancerous tissue (for example, through release of molecules that can prevent the immune system from killing tumor cells). While uncontrolled growth is a signature of all cancers, the reasons for this growth—and how they achieve it—can be very different from cell to cell.

What exactly causes cells to become cancerous?

At its most fundamental level, cancer is the result of DNA mutations, which are alterations to the genetic blueprint that provides instructions for our cells to grow, function, and reproduce. DNA mutations can occur in several settings. First, whenever cells reproduce, or divide, they make a copy of their DNA to pass on the same genetic code to the “daughter cells”. This process is not always error-free – sometimes mistakes are made during the copying process. In addition, DNA can also be damaged by environmental stressors, like UV radiation from the sun or chemicals in cigarette smoke (Figure 1).

Figure 1: Environmental Contributions to Cancer. DNA-damaging stressors like tobacco, alcohol, and ultraviolet light can cause cancer.

Since our DNA is the instruction manual for all cellular processes and activity, mutations can wreak havoc on the normal functions of a cell. Oftentimes, when the mutation has a deleterious effect, the cell realizes that it’s dysfunctional and kills itself in order to preserve the integrity of the organism. Other times, though, the mutation has a domino effect that can lead to cancer. For example, imagine that a mutation occurs in one cell (termed the ‘founder’ cell) that allows it to grow and divide faster (Figure 2). This increased division increases the likelihood that additional mutations will occur, due to the inherent error in cell division. The continual growth and mutation of this group of cells can eventually lead to a large, diverse mass of cells that form a cancerous tumor.

Figure 2: Cancer Develops via Sequential Mutation. Cancer developing from a founder cell, which has acquired a mutation that drives uncontrollable division and increases likelihood of developing further mutations.

Cancer and evolution go hand in hand

The war against cancer has pulled in researchers from all fields of science – from molecular biology to engineering and physics. It is the ecologist’s viewpoint, however, that has generated the newest shift in our understanding of cancer. In ecology, the term evolution describes how organisms that develop mutations to better meet the challenges of their environment are more likely to survive and have offspring. Over the course of many lifetimes, beneficial mutations can add up to create new species.

Since cancer is a disease driven by DNA mutations, its story is also one of evolution. Cancer cells that develop harmful mutations to themselves experience decreased growth and reproduction, and over time can disappear from the tumor. Other mutations may have no consequences, but some can make cancer cells reproduce faster or provide a protective edge against harmful substances in their environment. These cancer cells will, over time, make up a larger and larger part of the overall tumor.

When we treat cancer today, we often use chemotherapies that aim to stop cell division. However, cancer cells have an edge against these drugs. Some can leverage their newly acquired DNA mutations to increase the rate at which they break down and deactivate the therapy. Others become better at pumping the drug out of the cell. Some can even migrate into areas of the body that are less accessible to the drug. Understanding how different cancer cells evolve and respond to treatment can help us predict and prevent drug resistance from happening.

Turning evolution against cancer

Technologies like DNA barcoding, which uses synthetic DNA sequences to tag and track individual cancer cells, are helping us deconvolute the evolutionary patterns in different cancer cells. This is because when cancer cells divide, the barcode is replicated along with the rest of the cell’s DNA, allowing us to follow entire family trees (cancer lineages) that descended from one initial cancer cell.

A practical way that we can study cancer evolution is by observing how these cells respond to staged stress scenarios outside of the patient. For example, we can grow them in an artificial environment like a Petri dish and treat them with a chemotherapeutic agent (Figure 3). As intimated by the famous term “survival of the fittest”, originating from Darwin’s evolutionary theory, those cancer ‘families’, or lineages, that can best thrive in this toxic environment will be represented in the highest proportion. Less successful cancer lineages will be found in trace amounts or disappear completely. Recent improvements on DNA barcoding have even given us the ability to isolate live cells from a particular lineage of interest to study them more closely. By analyzing the surviving cells and studying their differences, we can determine the different mutations that contributed to their growth advantage.

Figure 3: Tracking Cancer Evolution. DNA barcodes can be introduced into cancer cells by packaging them into viruses which are used to infect the cells. During infection viruses integrate their content, including the DNA barcodes, into each cancer cell’s DNA. Barcoded cells can be tracked over the course of treatment: cells that are more abundant after treatment (blue) were best at surviving in the face of therapy, while cells that disappear from the population (green) were more sensitive to treatment.

These evolutionary experiments can tell us a lot about how cancer cells will react inside the patient’s body. They can inform what drugs we should use – and in which combinations – to better attack cancer or block off potential escape routes. We can design drug regimens that target existing mutations and drive cells carrying those mutations to extinction. We might even be able to prevent mutations that are likely to arise (a process called ‘evolutionary herding’).

In 2020, the war against cancer rages on. However, we’ve also gotten smarter. Technologies like DNA barcoding continue to add to our understanding of how cancer works, and with every new discovery, our arsenal of drug treatments grows ever larger. We now understand that cancer is a disease of constant evolution, and that it will take more than a silver bullet to beat it. Tagging and tracking can help us learn how.

Catherine Gutierrez is a sixth-year MD/PhD student in the Biological and Biomedical Sciences Program at Harvard Medical School.

Aparna Nathan is a third-year Ph.D. student in the Bioinformatics and Integrative Genomics program at Harvard University.

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