Leanne Li’s unconventional idea, that cancer cells might interact with neurons, was once dismissed. Now her lab is merging cancer biology with neuroscience, and revealing a previously hidden layer of tumour complexity, with electrifying implications.
Leanne Li's lab at the Crick. Credit: Christopher Agathangelou.
“I always wanted to do something outside the box, but people didn’t believe that my ideas would work,” says Leanne Li, leader of the Crick’s Cancer-Neuroscience Laboratory.
That was five years ago, before her interview to join the Crick. At that time, Leanne had spent months preparing for the interview. She had carefully prepared her answers and tailored her research proposal to match what was considered the safest route to success – working on fashionable topics in cancer research.
On the morning of the interview, however, during a brief meeting with the Crick’s director, Paul Nurse, which was meant to discuss her career at the Crick, she unexpectedly found herself confiding to Paul her long-lasting desire to work on science that truly fascinated her – rather than jumping on the ‘hot topics’ bandwagon.
Later that day, just five minutes before the interview, Paul appeared with a big smile, and said, “There’s a change of plan – I want you to talk about only one thing that really fascinates you, research where you truly believe in the science.”
“I was completely shocked, because usually we pitch three different research projects,” remembered Leanne, “but none of those projects I’d prepared actually fit with Paul’s criteria.”
“My mind went blank, and I thought, what should I do now?”
“Within those thirty seconds I had to decide, should I go for the well-prepared, ‘safe’ projects, or should I go for my crazy idea.”
Leanne’s ‘crazy idea’ was about a relatively uncharted area of science: the interaction between cancer and the nervous system, and whether that could one day be harnessed to treat the disease.
“It was an unprepared project. But it was the scientific dream that has inspired me for the past decade.”
“And I thought, OK, where else but the Crick could I do what I really want to do in science?” says Leanne.
She went for it, got the job, and today, that ‘crazy’ idea has now become a hot topic in cancer research.
The path that Leanne took to studying the cancer-nervous tissue interaction began in Switzerland around fifteen years ago, when she did her PhD with renowned cancer biologist Douglas Hanahan.
Over 40 years ago, Hanahan had pioneered one of the very first genetically engineered mouse models of cancer, generating a mouse strain with a particular susceptibility to pancreatic neuroendocrine tumours (PanNETs).
As his PhD student, Leanne used this model to study PanNETs and discovered, surprisingly, that their ability to spread relied on a well-known signalling pathway involved in learning and memory, usually active in brain cells.
This led her to start up a longstanding collaboration with a neuroscientist at Cambridge, Hugh Robinson. “Hugh painstakingly taught me the basic concepts in neurobiology, and introduced me into the field of electrophysiology,” she says.
Later, as a post-doc, she moved to MIT where her postdoc supervisor, Tyler Jacks, another giant in cancer research, supported her in shifting her focus to lung cancer.
So when Leanne started at the Crick, she took advantage of her past training in both pancreatic and lung cancer research, combining cancer biology and neuroscience to investigate how tumours communicate with the rest of our body.
“At the Crick, I’m supported and encouraged to do bold and creative research,” says Leanne. “There are so many neuroscientists at the Crick, and I spend quite a lot of time with them, embedded in their labs, discussing topics and learning their techniques. I’m interested in gaining a different perspective of cancer through their research lens.”
Recently, members of Leanne’s lab, post-docs Paola Peinado, Marco Stazi and Claudio Ballabio, showed for the very first time the direct, causal evidence between electrical activity and cancer progression. They found that certain lung cancer cells can generate their own electrical activity and build their own electrical network within a tumour. This network appears to exist independently of the body’s main electrical network, including the nerves surrounding the tumour.
This work has focused on one of the most aggressive types of lung cancer called ‘small cell’ lung cancer, a form of the disease in which tumours are often made up of two distinct subtypes of cancer cells, neuroendocrine cells - which have neuron-like features - and non-neuroendocrine cells that play a supporting role. It’s mainly the activity of the neuroendocrine cells that drives the tumour’s ability to growth and spread.
Leanne’s lab noticed these two cell types seemed to have a similar relationship mirroring that of two types of cells in the brain - neurons and astroglia. Neurons are the main cell type generating electrical signals, while astroglia are ‘housekeeping’ cells that support them.
And just as in the brain, in small cell lung cancer they found that the non-neuroendocrine cells were fuelling their neuroendocrine neighbours with a metabolite called lactate, allowing them to generate electrical signals which, in turn, drive tumour growth.
“We knew that some cancer cells can mimic neural behaviour, but we didn’t know how developing an independent electrical network might impact the disease outcome. By combining neuroscience and cancer research techniques, we’ve been able to look at this disease from a different perspective,” says Leanne.
“There’s still a long way to go to understand the biological impact of this electrical activity, and the specific disease mechanisms that make the tumour more aggressive and harder to treat. But we hope that in understanding the way these cancer cells are fuelled, we can also expose vulnerabilities that could be targeted with future treatments,” she adds.
This latest research has opened many future research ideas, as well as possibilities in investigating therapeutic opportunities and translating them into real-world treatments. Even so, Leanne says that there are many other ideas that she wants to pursue.
Paola Peinado Fernandez, Marco Stazi, Leanne Li and Claudio Ballabio in the lab. Credit: Christopher Agathangelou.
“I'm potentially moving slightly away from studying electrical activity within tumours themselves - not because it's not interesting, but because what really excites me is the unknown. So now we’ve proved that electrical activity can directly drive cancer progression, what’s the next big mystery in the field?” she says.
One area she’s looking at next is to ‘zoom out’ and study the cells, molecules and vessels that surround a tumour – the so-called ‘microenvironment’. “I want to know and how the nervous system is impacting the whole construction of the microenvironment, how that is impacting therapeutic resistance,” says Leanne. “And then ultimately, we want to look at the brain itself. How is the brain sensing, monitoring, and responding to the tumour formation? Could we one day treat cancers by treating the brain?
“There are just so many other things that are unknown and I want to go for those.”
Science from inside the Crick.
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