Each Cancer Has Its Origin Story. Just Ask a Cell’s ‘Diary’

Picture an event that changed everything. When did it begin and why? Historians might answer this question by delving into the past and studying photographs, letters and diaries. These first-hand accounts are crucial evidence which provide a raw and unfiltered view of events as they occur, helping reconstruct the past in order to explain and deal with challenges in the present.

What if we could do the same for cancer? By exploring the experiences of cells at the very starting point of cancer, we can better understand the behaviour of the disease, how it might spread, and how to best eradicate it. Delving into the history of cancer is critical for identifying the conditions which give rise to tumour-initiating cells, and, like finding the starting point of a wildfire, help put in measures to stop it from happening.

Like people, individual cells also keep a diary. Instead of paper, cells write on top of DNA, the blueprint of life, and instead of a pen, they use enzymes. Like an editor making changes on a manuscript, enzymes write or erase chemical tags known as DNA methylation marks. This is a fundamental biological process which can tune DNA’s activity.

Researchers can use these diary entries, also known as the DNA methylome, to get to know a cell’s personal history. With the ability to scan many different cells at once, researchers can identify the rare number of cells which might behave differently. These cells might be writing or erasing words in a different pattern, a behaviour that could correspond to diseases such as cancer.

However, the human body has trillions of cells, and any changing behaviour or pattern that is characteristic for the onset of a disease is like looking for a needle in a haystack. To detect this properly, we need technology able to read many cells simultaneously. But despite the DNA methylome being predicted as far back as 1948, efforts to study it at scale have remained out of reach. So, what’s holding the field back from contributing to a new age of medicine?

Dr. Renée Beekman, Group Leader at the Centre for Genomic Regulation, is an expert in epigenomics, a field which aims to understand DNA’s activity. In a perspective published recently in the journal Frontiers in Molecular Biosciences, Dr. Beekman and PhD students Leone Albinati and Agostina Bianchi outline the potential of the field in helping pinpoint the origin of cancer, and the obstacles researchers have to overcome to get there.

Millions of pages to decipher inside each cell

To read a cell’s diary, or its DNA methylome, researchers have to use a single-cell DNA methylation sequencing technology. This technique involves isolating individual cells, extracting DNA, and then using a method to determine the methylation status of the building blocks of DNA across the genome.

However, extracting the maximum amount of information possible using this technique is a huge technological feat. DNA is formed of different molecules or ‘letters’. Inside every human cell, there are 58 million instances of the letter C followed by the letter G – the majority of which are methylated. This is a huge volume of data to generate and process – and that’s just for one cell.

According to the Guinness World Records, Marcel Proust’s 13-volume A la recherche du temps perdu is the world’s longest novel. At 9.6 million letters long, we would need a novel six times bigger just to read CpG methylation. “To find meaningful patterns that inform the origin of cancer we need to chart many DNA methylation sites in thousands of cells. That is the scale of the task we’re up against,” says Agostina Bianchi, co-author of the paper.

While this sheer volume of data can be processed and stored correctly, it may be incomplete. This is because current methods can degrade DNA while reading it, leading to a loss of information for individual DNA methylation events as they are collected from the cell and transferred to an experiment and then a computer.

These technological limitations mean that historically, researchers have only been able to capture a random snapshot of a small set of DNA methylation sites in a few thousand cells. In other words, we can only randomly read parts of a cell’s diary, and even then we do not fully understand all the entries and miss out on meaningful information.

“We need to find ways of capturing the informative part of the diary in a systematic manner and interpret its nuanced entries before we can harness its full potential,” says Leone Albinati, co-author of the study.

Glimmers of hope

Despite the huge technological obstacles to overcome, scientists are making important progress in the field. Dr. Beekman has recently built a new tool that can chart DNA methylation patterns at scale. Alongside Dr. Lars Velten, also a Group Leader at the Centre for Genomic Regulation, her team developed scTAM-seq, a new method that can study subsets of DNA methylation sites of interest in up to 10,000 single cells at once, between 25 and 100 times more than what was previously possible.

“It works by focusing on the specific parts of DNA that are most likely to change, rather than trying to look at everything, making it an efficient and powerful strategy to look for rare types of cells, including those that may explain the origin of cancer,” says Dr. Beekman.

sc-TAM-seq is helping the field advance because it can study a lot of cells without being too expensive. As researchers around the world continue to develop similar tools, the field is expected to become even more efficient and cost-effective.
Other techniques that allow researchers to study the DNA methylome alongside other layers of information, such as RNA molecules, will provide an even deeper insight into what's happening inside a cell. “The transcriptome explains what a cell does at present. Combining this information with information from the past can reconstruct the history of how it got there. We want to be able to spot the ‘life-changing’ events which forever alter a cell, for example to trace how it turns into a cancer cell,” explains Dr. Beekman.

“Thirty years ago, we could not imagine creating a map of all the letters of the human DNA sequence, yet today it is a common good that is easily accessible to biomedical research. Right now we cannot imagine reading all the informative parts of the DNA methylome across thousands of single cells at once. However, technological innovations will bring us closer to this goal little by little,” concludes Dr. Beekman.