What patients can teach us about cancer

For Ayesha Noorani, research begins in the clinic – with something she notices, a pattern that begins to emerge or a question from a patient that she cannot answer.

“Why me?” asked one of her younger patients with gastric cancer. He was fit, an endurance athlete, had never smoked and felt he had done everything right. Ayesha did not have the answer. But the question stayed with her and helps to drive her research.

“A lot of my questions are guided by what I see clinically,” she says. “The questions come from the patients, and what’s important to them.”

Ayesha is a clinician scientist and cancer surgeon based at Addenbrooke’s Hospital in Cambridge, where she specialises in cancers of the oesophagus and stomach. Her time is split between operating on patients and leading her own research group as a Career Development Fellow at the Sanger Institute.

The two sides of her work are different. Surgery can mean spending eight hours in an operating theatre, working on some of the most complex and high-risk cancers. Meanwhile, the lab offers a quieter space to think, ask questions and brainstorm with other experts in the field. But for Ayesha, they are closely connected. “For me, one thing gives purpose for the other and vice versa,” she says.

Ayesha’s research focuses on understanding how cancer develops, and particularly on identifying changes that occur before cancer becomes visible under the microscope.

One of the conditions that first drew her attention was achalasia, a rare disorder in which the oesophagus stops contracting properly. Food can build up in the oesophagus, which becomes enlarged. People with the condition have up to fifty times higher risk of developing oesophageal cancer than the general population.¹ Yet despite that increased risk, these patients are not routinely monitored for developing cancer.

“They’re quite an underrepresented group,” Ayesha says. “It can take years for them to receive a diagnosis, and they can often feel like the ‘left-behind group’ in oesophageal diseases.”

Her interest in the condition was not simply scientific. It was shaped by what she saw happening to people in her clinic. She remembers one patient in particular, a woman in her 50s who had achalasia and developed an aggressive oesophageal squamous cell cancer – the predominant type of oesophageal cancer globally.

“I remember thinking during the diagnostic endoscopy, could we have seen this coming earlier and could this have been prevented.”

That question – how did this happen and could we have seen it coming? – became one of the central questions guiding her research.

Ayesha and her colleagues began looking at tissue that appeared completely normal under the microscope. They wanted to know whether there were already genetic changes hidden within those apparently healthy cells that could indicate a future cancer risk.

Using techniques including laser capture microdissection, spatial transcriptomics and NanoSeq technology, they were able to isolate tiny areas of epithelium within the oesophagus and examine them in much greater detail. The precision was important because the changes they were looking for were incredibly rare.

“If you don’t have resolution, it’s a needle in a haystack. You would just miss it,” explains Ayesha.

To understand whether these changes were specific to achalasia or might occur more widely in conditions that affect how the oesophagus contracts and allows food to pass, Ayesha used Chagas disease – a tropical illness caused by the parasite Trypanosoma cruzi – as a comparative group. Working with researchers in Barretos Cancer Hospital in Brazil, led by Professor Rui Reis, her team studied the damage on the lining of the oesophagus in Chagas disease: the muscle stops working, the oesophagus becomes enlarged, and the risk of cancer increases. By comparing them, the team could look for changes that were associated with the development of cancer rather than with the underlying disease itself.

Within these diseases, they found that genetic changes precede any changes under the microscope, revealing an intermediate state that could potentially be detected, monitored or intercepted before cancer develops.

But Ayesha wanted to know whether this was unique to these diseases and so, her current work is looking at the normal tissue next to cancer to see if these changes exist.

“With achalasia, you have this model where the likelihood of cancer is higher,” Ayesha explains. “It’s like a time lapse movie – you have a greater chance of capturing some of those intermediate stages. It’s harder to capture in people otherwise because the time to develop a cancer is shorter.”

Achalasia, in other words, gives researchers a rare opportunity to observe the process of cancer development over a longer period, making it easier to identify the changes that happen along the way. If these early changes can be detected through approaches such as oesophageal brushings to collect cellular samples from the lining of the oesophagus, they could potentially help identify patients who need closer surveillance, allowing cancer to be detected and treated much earlier.

"If you treat it earlier, they’ll have a normal life", she says.

As this work developed, Ayesha noticed another change in the people coming through her clinic. Some were younger than she would normally expect, and she was also seeing more women than is typical for cancers that traditionally have a higher male-to-female ratio.

“These women were in their 40s, many with children, at a point in their lives when they should be enjoying their careers and family life, but suddenly cancer just completely takes over.”

The numbers in these cancers are relatively small, so the trend can be difficult to see in published data. But Ayesha kept noticing it. So, she began asking whether this was a genuine shift and, if so, what might be driving it.

That observation has now become another strand of her research. Her PhD student, Dr Unaiza Waheed, co-supervised with Professors Sir Mike Stratton and Rui Reis, is investigating why people are developing upper gastrointestinal cancers at younger ages and why more women appear to be affected than before, combining epidemiological data with the molecular landscape of the tumours. Her work is based on samples from the UK and from Brazil – a hotspot for gastric cancer – with collaborators at Barretos Cancer Hospital. The team also recently published its findings on clinical trends in the UK.¹

It is another example of the way Ayesha works: noticing something in the clinic, asking whether it represents a wider pattern and then taking that question into the laboratory.

“You get the snippets of where the interesting questions might be, or where there’s a need in the field, and where you can contribute the most.”

Her team is also investigating why people with aggressive cancers respond differently to treatment, including whether differences in the immune environment around tumours might help explain those responses.

Using spatial transcriptomics and other approaches, they are looking not just at what is happening within a tumour, but where different cells are located around it.

“You’ve got your whole organ, for example, stomach or oesophagus, but the tumour only arises in one part,” Ayesha says. “The clue of why it doesn’t arise in another part, where the exposures are shared, I think, is equally as important and points towards resilience and a route to avoiding the cancer.”

For her, understanding what protects healthy tissue may be just as revealing as understanding what allows cancer to develop.

The Noorani group pose for a photo together during a team buiding day. From left-right: Dr Hussein Farah, Johanna Hindmarsh, Will Knight, Dr Unaiza Waheed, Dr Ayesha Noorani.

Credit: Ben McDade / Wellcome Sanger Institute

Behind the cancer

Ayesha’s instinct to ask why cancer develops in one person and not another is also rooted in her own experience.

Her uncle developed oesophageal cancer in his 50s. He was her father’s younger brother, part of a large Pakistani family with many medics, yet his diagnosis was missed.

Ayesha was a medical student at the time and spent a lot of time with him through his illness. She saw his chemotherapy, the blocked lines (intravenous catheter that delivers chemotherapy), the hair loss – but also what the disease did to the person she knew and those around him. “He was a jovial, larger-than-life character,” and she saw how much the cancer changed him.

She also saw the impact on his young children and the wider family, too.

“It has this massive ripple effect,” she says.

The experience changed the direction of her career. At the time, she had been considering becoming a vascular surgeon, but cancer raised questions she felt compelled to pursue prompting a pivot in her surgical career.

She became interested in why cancers spread and how they evolve as they move through the body according to evolutionary principles. The same principles now underpin her research into normal epithelium, where early changes are harder to detect, but where the tissue retains a record of the exposures it has accumulated over time.  More broadly, she realised she wanted to work in a field where she could know the patients and their families.

“I like knowing the patients, knowing their families, knowing their stories,” she says. “I’ve always liked stories and felt privileged to hear them. For me, that has given my work a bigger sense of purpose.”

That same instinct now runs through her research. The questions may be molecular, but they are rarely abstract. They come from people.