Science Snaps: rearranging our understanding of the cancer genome

Like many things, our DNA can change over time.  

Changes to our cellular blueprint can come in many different forms – from single errors and small gains or losses to large scale rearrangements of the code. This kind of complexity can drive tumour growth and is a typical marker of a cancer cell.  

One of the most genomically rearranged cancers is an aggressive type of ovarian cancer, called high grade serous ovarian cancer. And it’s a cancer that PhD student, Carolin Sauer, wants to learn more about. But instead of focusing on individual genetic changes, Sauer is more interested in “how some of these patterns or genomic rearrangements might come about”.  

She hopes that understanding the mechanisms behind these changes might be able to help us target specific processes to develop new ovarian cancer treatments.

Focusing on centrosomes

“Ovarian cancer, and particularly the type I work on, has a very complex genome and a high degree of chromosome instability, which makes it very difficult to develop targeted treatments,” says Sauer, who works at the Cancer Research UK Cambridge Institute. She was always interested in studying cancer and when it came to picking her PhD, she was drawn to the unique challenge of working on such a complex cancer type.

Sauer has centred her research around a small but vital part of how cells split their DNA when they divide – the humble centrosome. 

“A lot of people don’t know what they are, but they are these tiny, tiny organelles. Like a little ball of protein,” she explains. “They play an important role in making sure cell division runs smoothly.”  

Because of the vital role centrosomes play when cells divide, any changes to this essential process could introduce mistakes into the DNA.  

Sauer explains how we already know that a lot of cancers have centrosome abnormalities, such as centrosome amplification, which means that you have more centrosomes than you need.

During her PhD, Sauer has a lot of questions about centrosomes and the role they’re playing in ovarian cancer. But the very first question she started with was “are centrosome abnormalities even present in ovarian cancer?”  

A numbers game 

To answer this question, Sauer has been carrying out immunofluorescence staining on tumour tissues in the lab. “I started off with samples from around 120 patients with high grade serous ovarian cancer.”  

From these amazing images, Sauer was able to calculate a ratio of the number of centrosomes per cell. In her stains, the centrosomes light up in yellow. 

Looking at the picture below, Sauer says, “this sample is from a patient-derived organoid, so this is actually not a tissue sample, but you can see the centrosomes here very clearly. “If you zoom in a bit you can see some cells that have more than one or two centrosomes and that would be a centrosome amplified cell.” 

High grade serous ovarian cancer cells stained for centrosomes. The centrosomes can be seen as the small yellow flecks. In this example, around 1 in 3 cells contain more than 1 or 2 centrosomes and are said to be centrosome amplified, a condition that results in increased chromosome instability and genomic complexity.

She has discovered that around 70% of high grade serous ovarian cancer samples had some degree of centrosome amplification. “Meaning that quite a large fraction of patients with this type of ovarian cancer have abnormal centrosomes,” Sauer comments.

Furthermore, 45% of the tumours also had physically enlarged centrosomes when compared to non-cancerous control tissues.  

What came first, the chicken or the egg?  

The next step in Sauer’s research is to understand the relationship between centrosome amplification and the rearrangement of the genome that we commonly see in cancer cells. “It’s a bit like the chicken and the egg question, which one came first?” she explains. “It’s trying to understand whether centrosome amplification or abnormalities drive chromosome instability and genetic complexity.”

This idea has been explored before. In the 19th Century, Theodore Bevori introduced the idea that centrosomes have a role to play in inducing cancer. But stronger evidence is still needed to understand the timing of these changes.  

“Because centrosomes are highly involved in mitosis and chromosome segregation, you would think that the presence of centrosome abnormalities or centrosome amplification would result in chromosome segregation errors, lagging chromosomes and larger rearrangements to the DNA … so I would definitely expect these cases to have a more instable genome,” Sauer says.  

High grade serous ovarian cancer tissue section stained for centrosomes to allow detection of centrosome amplification. Centrosomes are stained in yellow. Centrosome amplification is thought to be linked to chromosome instability and genomic complexity which further drives tumour growth and evolution.

An unusual finding 

Sauer recalls how, so far, the research published around centrosome amplification reports on the relatively poor survival of such patients. 

However, Sauer’s results were quite surprising. “I found that in cancers that have a very complex genome with high chromosome instability centrosome amplification actually seems to favour survival,” she says.  

Sauer and her team are trying to understand this complex relationship. One hypothesis is related to how a cell with high genomic complexity and centrosome amplification, already under stress, is more sensitised to the additional stress of chemotherapy. 

Promisingly, her recent finding that centrosome abnormalities are fairly common in high grade serous ovarian cancer and may be an important biomarker for therapies that target cell division.

It’s early days for Sauer, but her and her team are working hard to define how centrosome amplification may indicate specific vulnerabilities in the cancer that could be exploited by treatment.  

Lilly