Up close, cancer is a disease of rogue cells with corrupted DNA. But zoom out and it’s far more: it rewires our biology on multiple levels, from neighbouring tissue to whole-body systems. Unravelling this vast complexity is forging new collaborations across scientific fields and opening up new opportunities to tackle the disease.
Zooming out: a tumour interacting with neighbouring cells, distant organs and whole-body systems like the immune and nervous systems. Illustration: Mark Harris.
“In a way, everyone here works on cancer, even if they don’t think of themselves as ‘cancer’ researchers,” says the Crick’s Ilaria Malanchi. “We’re all trying to solve the mysteries of how cells work together to make an organism.”
Cancer develops when cells stop cooperating and subvert the rules that keep our bodies functioning. Understanding how this happens has, historically, focused in on the cancer cells themselves: their corrupted DNA riddled with errors that imbue them with superpowers like immortality, the ability to spread and – most devastatingly – the ability to evade even the most sophisticated treatments. Indeed, most lay definitions describe cancer simply as: “a disease caused by rogue cells multiplying out of control”.
Studying these cells has, without doubt, transformed care for people with cancer, with a slew of targeted drugs and advanced diagnostics. As a result, outcomes for people with cancer have continued to improve.
But this only got us so far. Worldwide, the disease still claims around 10 million lives each year, and profound mysteries remain. Why do some cancers seem to spread to particular organs? How do tumours become resistant to therapies? Why do all adults carry countless thousands of mutant cells, only a tiny proportion of which ever develop into a tumour?
In search of answers, researchers are stepping back from studying cancer cells themselves and exploring how they interact with the rest of the body.
One level out, researchers have been probing the local exchanges between a tumour and its immediate neighbours. Zooming out further, and they’re eavesdropping on cancer’s dialogue with more distant organs such as the lungs and liver, which paves the way for it to spread. And at the broadest view, they’re studying how a tumour manipulates, and is manipulated by, whole-body ecosystems like the nervous and immune systems.
Cancer, it appears, is much more than just mutant cells. As researchers look for answers across traditional disciplines, a much bigger picture is emerging: a disease caused by malfunctions in the body-wide systems that keep us healthy.
“I would define ‘cancer’ as the inappropriate activation of biological programmes,” says Ilaria. These are programmes linked to embryonic development and wound healing that, she says, “ultimately change the state of our tissues, organs and ultimately our whole body.”
“Cancer is just a sort of extreme physiology,” agrees Ilaria’s colleague Caroline Hill, one of the Crick’s deputy research directors and leader of the institute’s Developmental Signalling Laboratory. She shuns the label ‘cancer researcher’, instead describing herself as “a cell, molecular and developmental biologist who is interested in cancer and other diseases.”
By integrating insights from developmental and cancer biology, Caroline’s team recently begun to unravel an enduring biological paradox: how a particular molecular process can both fuel and suppress cancer.
Caroline’s work focuses on the messages exchanged by neighbouring cells, particularly a group of 30-odd messenger molecules, or ligands, known as the transforming growth factor beta (TGF-β) superfamily. These bind to receptors on neighbouring cells, activating internal relay proteins called SMADs, which travel to the nucleus and switch on groups of genes that alter cell behaviour.
The first TGF-β family members evolved alongside multicellular life some 600 million years ago and appear to have helped pattern early body plans – determining, for example, the way a snail’s shell coils or the axis of symmetry in primitive sponges.
“In humans, members of this family play a range of very different roles,” says Caroline: they’re intimately involved in embryonic development and wound healing. They also crop up in cancer: defects in SMAD relay proteins are found in several types, particularly bowel and pancreatic cancer.
But, until recently, exactly how TGF-β family members contribute to cancer has been difficult to untangle.
Cancer-linked genes generally fall into two classes: oncogenes – mutated proteins which can accelerate cell growth; and tumour suppressors – brakes that keep growth in check unless damaged.
For decades, researchers developing precision therapies followed a simple formula, says Caroline: “All we thought we needed to do, particularly for tumour-promoting molecules like oncogenes, was to find out how to inhibit them to stop the cancer growing.”
But depending on the conditions, the TGF-β pathway seems to be able to act as both accelerator and brake. TGF-β itself was first isolated in the early 1980s from cells, as a molecule that caused other cells to ‘go rogue’ and behave like cancer cells. But then, shortly afterwards, researchers discovered that adding TGF-β to lung cells actually made them stop growing. “This caused a huge amount of confusion – there seemed to be two contradictory activities,” says Caroline.
This dual role hampered efforts to develop drugs targeting TGF-β signalling. Caroline’s recent work, however, has begun to resolve the paradox, by teasing apart the roles of different TGF-β family ligands, and which neighbourhood cells produce them.
The issue, says Caroline, is that while overactive TGF-β-family signalling was clearly involved in cancer, “people weren’t really thinking about which cells were the source of the ligand, nor what other cells it might be activating.”
A way forward started to emerge from studying embryonic development, as Caroline’s team spotted subtle differences in the type of signalling evoked by different TGF-β-family ligands. Then, comparing these with cancer, they began to suspect that TGF-β itself might not be the key ligand. Instead, her lab pulled focus to another family member, activin, that had received relatively little attention from cancer researchers.
In particular, they homed in on support cells called fibroblasts, which become activated in cancer and secrete signals that can help nurture a growing tumour.
“In our mouse cancer models, we discovered that fibroblasts weren’t actually secreting any TGF-β – but they were pumping out a heck of a lot of activin,” she says. This activin seemed to be doing several cancer-promoting things, including repressing the local immune system, and triggering construction of a strong protective barrier around the tumour: the extracellular matrix.
But would blocking activin’s effects reverse this? To find out, Caroline’s team set about developing a precision antibody that could bind and neutralise it.
Initially, they tested it in mice with pancreatic tumours that had a fully functional activin pathway. “To our dismay, the anti-activin antibodies actually made the disease worse,” she says. While blocking activin had, as expected, relieved its repressive effect on immune cells, they realised the ligand had also been doing something else – something paradoxical: its signals were also being picked up directly by the cancer cells, who interpreted it as a growth suppressor – and this was acting as a partial brake on their proliferation.
So, while the antibody blocked activin’s repressive effect on the immune system – causing tumours to fill with immune cells – it also switched off the ‘tumour suppressive’ signal to the cancer cells themselves and this was enough to counterbalance the immune attack: overall, tumours grew even larger.
But a more promising situation arose in mice bearing more aggressive tumours that lacked the SMAD4 relay protein, as occurs in around a third of patients with pancreatic cancer. These tumours can’t ‘hear’ suppressive signals from TGF-β-ligands like activin. So, in these tumours, activin’s sole effect was to suppress the immune system.
When Caroline’s team gave these mice their activin-blocking antibody, things were much more positive: the tumours shrank substantially, as killer immune cells flooded in.
It’s a finding that suggests that blocking activin might be an effective treatment strategy, but only in the third of pancreatic cancer patients whose tumours lack SMAD4.
Caroline’s discovery, teasing apart the tumoursuppressive and tumour-promoting effects of TGF-β-family proteins in cancer, could revive interest in targeting them. Drugs aimed at TGF-β itself have so far proved disappointing, and much of the pharmaceutical industry has moved on. “People have been burned,” says Caroline. “But maybe part of the reason for failure has been that early TGF-β drugs weren’t targeting the right patients. And maybe they were targeting the wrong target.”
By unpicking the local signals exchanged between fibroblasts, cancer cells and the immune system, Caroline’s work looks set to change that.
If Caroline studies conversations within tumours, her colleague Ilaria Malanchi asks a different question: how do tumours communicate across the body, allowing them to spread to distant organs and tissues? Again, it seems that exchanges between cancer and non-cancer cells – and the reactivation of dormant cellular programmes in both – are key.
To metastasise, a cancer cell must survive in a hostile environment: a foreign organ or tissue that lacks the nurturing signals present in the tumour’s birthplace. But for Ilaria, who leads the Crick’s Tumour-Host Interaction Laboratory, the question is less about the cancer cell than the location, or niche, to which it spreads.
“What makes an organ ‘fit’ for metastasis is still an open question and there are many things we don’t understand,” she says. However, evidence from her lab and others is revealing how cancer cells release factors into the bloodstream that somehow ‘pre-condition’ distant organs to receive them. “We describe it as tissue conditioning,” she says.
There seem to be two main mechanisms.
The first, which Ilaria calls ‘deterministic’ conditioning, is driven by tiny sub-cellular bubbles released by cancer cells called exosomes. These carry messenger molecules, including RNAs, that can switch genes on and off in cells that absorb them. These can be taken up by specific tissues (as dictated by their cargo), which become reprogrammed to be more receptive to metastasis.
The second mechanism, she says, is more serendipitous. “I’m more fascinated with how tumours trigger more general changes, which reawaken inflammatory and regenerative pathways in distant tissues that condition them for metastasis.”
Several years ago, working with a mouse model of breast cancer that spreads to the lungs, Ilaria’s team uncovered a central role for immune cells called neutrophils – previously underappreciated in cancer.
As cancer cells grew in the breast tissue, but before they’d spread, Ilaria’s team found that neutrophils began accumulating in the lungs. There, they secreted molecules called leukotrienes that conditioned the lung tissue to receive metastatic cells. Blocking neutrophils’ ability to produce leukotriene largely prevented the cancer from spreading.
More recently, as Ilaria’s team continued to study how tumours condition the ‘pre-metastatic niche’, they’ve developed a way to study lung cells that interact with breakaway breast cancer cells immediately after they arrive. “We were trying to identify the cells in a tissue that talk with the early infiltrating cell,” she says.
This led them to specialised cells that line the lung’s air sacs, known as AT2 cells. When grown in the laboratory, AT2 cells taken from cancer-bearing lungs appeared markedly more ‘stem-like’ than normal AT2 cells – they’d reactivated regenerative programmes that allowed them to create a supportive environment for incoming cancer cells.
“We think that, somehow, as cancer cells themselves deprogramme into a more primitive, ‘stem cell-like’ state, this state becomes reflected in the pre-metastatic niche, which also becomes more stem-like. And this allows both communities of cells – cancer and non-cancer – to access all sorts of developmental programmes that they normally can’t.”
Ilaria is now bringing these discoveries together to understand how signalling between a distant tumour, the immune system and local cells such as AT2 cells enables a cancer to spread.
Widening focus even further is revealing even more of cancer’s mysteries, according to Jose Adrover, who moved to the Crick from Johns Hopkins University in Baltimore in 2024 to establish the institute’s Cancer Macroenvironment Laboratory.
“Research in cancer has been changing from narrow to broad,” he says. “First, there was a focus on cancer as a disease of the cell, then on how these cells communicate with and affect all the cells around them – the microenvironment. My team is now focusing on the whole ecosystem: the ‘macroenvironment’.”
Among the mysteries Jose is exploring is why people with cancer, regardless of treatment, face a substantially increased risk of strokes, heart attacks and other cardiovascular events. “It’s actually one of the main causes of mortality in cancer patients.”
As with Ilaria’s work on metastasis, neutrophils appear to play a central – previously overlooked – role.
“Neutrophils have been hiding in plain sight,” says Jose, pointing to studies showing that, among immune cells found in tumours, the presence of neutrophils is associated with the poorest patient outcomes.
Produced in vast numbers by the bone marrow, neutrophils have traditionally been viewed as relatively simple bacteria-killing cells. “That started to change in the last decade,” says Jose. “We now know they also play all sorts of roles in the body’s ability to self-regulate.”
As well as engulfing bacteria and helping maintain tissue health, neutrophils possess a remarkable weapon, described as the immune system’s ‘atomic bomb’: neutrophil extracellular traps, or NETs.
“NETs are an indiscriminate way of killing things,” says Jose, “and they seem to allow a neutrophil to respond either when there are too many invaders to eat, or they’re just too big.”
To form a NET, a neutrophil dismantles its nucleus and unspools nearly two-metres-worth of DNA and accompanying binding proteins. Simultaneously, it dissolves the membranes surrounding microscopic granules that float in its cytoplasm in vast numbers, all of which are full of toxic proteins.
“Then they mix everything – the toxic stuff that they have within the granules, their DNA, all the binding proteins – and then rupture their external membrane to release this incredibly toxic mesh to the outside world, dying in the process. It’s a very efficient way of killing things, but one that has a lot of unintended consequences for the surrounding cells,” says Jose.
Early in his career, Jose studied neutrophils in cardiovascular disease, but after moving to the US in 2020, switched focus to cancer.
“One of the first things I did was use the tools I’d developed to study neutrophils in cardiovascular disease to look at cancer. And I spotted something strange: many of the tumours were absolutely packed with neutrophils making NETs. I told my supervisor: this is immunological mayhem. It makes no sense,” he recalls.
An even stranger pattern emerged: NETs consistently formed next to regions of necrosis – areas of dead tissue thought to arise inside fast-growing tumours as they outstrip their blood supply.
But the striking geometry of the necrosis suggested something else. “Why is this not random?” Jose remembers thinking as he looked down his microscope.
“Why are these NET-rich necrotic regions forming in these very strange shapes?”
It turned out that NET-induced damage was blocking the tumour’s blood vessels and this was actively causing necrosis. More unexpectedly, he saw that cancer cells bordering these damaged regions were reprogramming themselves into a more metastatic state, apparently attempting to escape the hostile environment. In other words, neutrophil-triggered necrosis seemed to be causing the tumour’s aggressiveness, rather than being a consequence of it.
The same mechanism also helped explain the long-observed link between cancer and cardiovascular disease: “We found that NETs from these neutrophils were causing blockages in blood vessels around the body, causing the sort of damage you see in cardiovascular disease,” he says.
But where were the hyperactive neutrophils coming from? Jose’s group discovered that growing tumours were releasing signals that travelled deep within the bone marrow, where they reprogrammed stem cells to super-charge neutrophil production.
More surprising still, the neutrophils damaging the blood vessels with their NETs appeared unlike any neutrophils previously seen in healthy adults – they lacked neutrophil’s hallmark ability to migrate out of blood vessels and into the body’s tissues. And, once again highlighting the crossover between cancer biology and embryology, Jose’s recent work suggests these represent a form of neutrophil seen only during embryonic development. His team is now working with colleagues across the Crick to understand more about them, including whether their production can be targeted therapeutically.
The way cancer seems to reprogramme bone marrow echoes Ilaria’s idea of ‘reflected stem-ness’: cancer does not simply reprogramme itself, but coaxes distant tissues into reactivating developmental states.
“It looks like cancer is a disease of ‘backward reprogramming’,” says Jose. “On an almost philosophical level, you start as a single cell, then you become an embryo, and then a foetus, and then an adult… and this incredible development potential you’re born with fades away as you get older. But as cancer develops, it pushes it back the other way, so the tissues reacquire the ability to run programmes from much earlier in your life.”
As researchers like Caroline, Ilaria, Jose and others at the Crick continue to probe cancer’s local, distant and whole-body effects, more seemingly disparate phenomena are beginning to fit into the same picture.
“Beyond its impact on the cardiovascular system, another effect of cancer is triggering a muscle-wasting phenomenon called cachexia,” says Jose. Recent discoveries suggest this is prompted, in part, by TGF-β family signalling, with activin a potential culprit, says Caroline Hill. “That may be another benefit of activin-targeting drugs: you might avoid or diminish cachexia.”
Another frontier, only just beginning to be explored, is how cancer interacts with the nervous system. Researchers have long known that nerves can grow within tumours, but only recently have techniques become available to study this in detail. The Crick’s Leanne Li, one of the first researchers to explore the field, was recently awarded a multimillion-pound Cancer Grand Challenge grant bringing together cancer biologists, neuroscientists, neuroimmunologists and others to push forward to this new horizon.
And looking beyond the body, the Crick’s Charlie Swanton has been investigating how tissue inflammation caused by environmental exposures such as air pollution can trigger lung cancer. Researchers now know that all of us harbour cells carrying cancer-associated mutations, yet only a tiny minority ever develop into tumours. Charlie’s work suggests air pollution triggers immune changes that allow these mutant cells to escape normal controls and expand. His team has also identified a protein signature in the blood, detectable up to five years before symptoms appear, that identifies people at elevated risk of lung cancer and other lung diseases.
Taken together, these discoveries show how understanding cancer means bringing together developmental biology, immunology, stem cell biology and neuroscience – communities of researchers sharing insights about the same underlying problem.
A good example comes from Jose’s own lab. The embryonic identity of his newly discovered neutrophils only emerged because a member of his group, Afshan McCarthy, had previously worked on embryonic development elsewhere at the Crick.
“She had that knowledge, we discussed it, and she decided to have a look. And that led to this whole concept,” he says.
Ilaria agrees.
“Because we’re all trying to solve the mystery of multicellular life, my colleagues are going to think about the same questions as me, but in very different ways – and that is going to be beneficial because we come from different angles to find the answers.”
The irony is striking. Multicellular organisms only exist because of the deep networks of cooperation between cells. Cancer succeeds by persuading them to cooperate again – but this time in service of the tumour. Understanding that corrupted cooperation is turning out to be just as important as cataloguing mutations – and the next generation of cancer therapies may therefore target not simply malignant cells, but the societies they create.
Charlie Swanton, Clinical Director at the Crick
A great deal of what we’ve achieved in cancer research at the Crick comes, paradoxically, from the fact that we’re not all studying cancer.
That’s what I love about this place. I can walk down a corridor and talk to someone working in developmental biology, tissue homeostasis, ageing or infection and immunity, and suddenly see a problem I’ve been thinking about through an entirely different lens.
"If you’re given a diagnosis of pancreatic cancer and I tell you that we have a new treatment that can extend survival from six months to twelve, your response is unlikely to be, ‘That’s wonderful.’ It’s more likely to be, ‘Are you telling me I may be dead in a year?’ That is the harsh reality of some cancers, despite the phenomenal progress we’ve made in treatment."
"Increasingly, our attention is turning to prevention. One of the great questions is whether we can intervene in the biological processes that make us increasingly susceptible to disease as we age.
There is remarkable science emerging around chronic, age-related inflammation, so-called ‘inflammaging’, and the possibility that it may provide a common thread connecting cancer with cardiovascular, neurodegenerative and other diseases of ageing.
AI is becoming central to how I think about these problems. It has helped me navigate an extraordinarily complex literature around inflammatory memory and understand how ideas developed in other areas of biology might apply to lung cancer. What became apparent is that many of the underlying biological rules are shared across systems. It illuminated a much broader world of tissue orchestration that I might otherwise have taken far longer to see.
There are very few institutes in the world with our breadth of disciplines combined with an explicit mandate to be curious and work together. I think this culture will be one of the keys to uncovering many more of cancer’s secrets and make the progress our patients deserve.
