When we think about cancer, we often picture cells that have lost normal control. But what’s less obvious is that they might not be using completely new machinery – they could be using the same systems our tissues depend on for normal repair.

During wound healing cells divide, migrate and change behaviour to close the gap. And at the centre of this response are stem cells and cell plasticity – the ability of cells to shift their identity or function when the tissue needs it. For example, specialised cells can dedifferentiate to a stem cell like state.

This plasticity is essential for healing. But under the wrong conditions, plasticity can also help cancer grow, spread or resist treatment. Understanding why repair is normally safe – and when it stops being so – is giving us new clues about how cancers initiate and how we might stop them.

Healthy epithelia contain multiple, spatially distinct pools of stem cells that maintain tissue turnover. Under steady-state conditions, these compartments operate within well-defined lineage boundaries and niche constraints. Injury disrupts this equilibrium. To repair damage quickly, stem cells lose this lineage restriction and enter a transient plastic state that resolve once the tissue heals.

When repair does not resolve

In healthy tissues, the activation of a repair programme is transient: stem and progenitor cells expand, inflammatory cues rise and fall, and the niche gradually re-establishes its usual boundaries. Difficulties arise when this return to homeostasis is delayed or fails.

Chronic wounds, persistent inflammation or repeated episodes of injury can hold tissues in a sustained regenerative state. Chronic injury may not create cancer on its own but can shift the competitive balance so that mutated cells already present in the tissue gain an advantage.

Under these conditions, the cellular features of repair and early tumourigenesis begin to converge. Both involve sustained inflammatory signalling, activation of fibroblasts, alterations in extracellular matrix composition and stiffness, and the adoption of cell states that fall outside normal lineage restriction. If such programmes remain active for a long time, the likelihood increases that cells accumulate mutations, acquire selective advantages or stabilise states that would normally be transient.

Another reason prolonged repair is also relevant here because it has been seen that some stem cells do not fully reset after injury.

Wound experience leading to memory

After wound healing, the regenerated epidermis looks similar to normal skin. However, the stem cells that contributed to regeneration do not return entirely to their pre-wound state. Instead, they retain an epigenetic memory of the inflammatory response – a molecular imprint that primes them for a faster and more efficient response to a secondary injury.

This memory is recorded through stable changes in chromatin accessibility. In skin, even a transient inflammatory episode leaves basal stem cells poised for faster re-epithelialisation upon re-injury. The mechanism for this involves stable enhancer remodelling downstream of IL-1/NF-κB and AP-1 networks. While beneficial for regeneration, such memory can become maladaptive when oncogenic mutations are present.

In the pancreas, epithelial inflammatory memory protects against recurrent damage but simultaneously increases susceptibility to tumourigenesis, consistent with a model in which primed cells more readily re-enter proliferative or plastic states. Parallel evidence in the gut indicates that inflammation can imprint intestinal stem cells, potentially altering their fate and competitiveness during subsequent repair; this may favour clonal expansion of mutated cells in chronically injured mucosa. In this way, we can see that injury leaves not only scars in the stroma but also molecular scars in stem cells. This extends the period during which repair programmes and somatic evolution can intersect.

In line with these observations, our laboratory is examining how tissue injury may affect the behaviour of different stem cell populations in the early steps of tumour formation. Distinct stem cell populations differ in their sensitivity to inflammatory cues and in the epigenetic memories they retain after repair. We are also exploring whether specialised cells that transiently dedifferentiate during wound healing acquire similar vulnerabilities, potentially broadening the pool of cells capable of initiating malignant transformation.

Why this matters for cancer research

Understanding wound repair through the lens of stem cell heterogeneity and plasticity offers several advantages for understanding tumour initiation. First, it can potentially help identify the origin of tumours by allowing the exploration of which cells are most susceptible to tumourigenesis when repair systems malfunction. For example, skin stem cells that normally respond to injury are the cells of origin in cutaneous squamous cell carcinoma.

Second, it offers mechanistic insight into how the microenvironment and extrinsic signals contribute to tumour initiation and progression. The idea that a “wound that never heals” might set the scene for tumour initiation is now supported by evidence.

Third, plasticity offers one explanation for tumour heterogeneity and therapy resistance. If a cell can shift its identity or adopt a distinct lineage state under stress, then it may evade treatments designed for a fixed target.

Finally, new therapeutic opportunities could open up if we can understand the signals that force plasticity in repair. Perhaps we can “steer” cells back to normal trajectories or prevent the plasticity that underlies tumour initiation. If, for example, we modulate inflammation, remodelling extra-cellular matrix, or alter niche signalling it might be possible to reduce tumour risk in chronic‐injury settings.

What’s next?

A key challenge is to distinguish normal regeneration from the earliest tumour-promoting changes. New single-cell and spatial methods are revealing how cell states shift during injury and how long they persist. Another advance here will be improved in vitro models of acute and chronic injury which are being developed to study how stem cells behave when niche signals fail to switch off. Identifying these early shifts could help us understand when plasticity becomes harmful.

Ultimately, the goal is not only to understand how cancer begins, but to pinpoint the precise moment when adaptive plasticity crosses a threshold and becomes destabilising.

Wound healing and cancer share many similarities. One restores order, the other disrupts it, but they both rely on stem cell plasticity, lose of lineage restriction and constant communication with the niche. By understanding why repair usually works smoothly and when it fails to resolve, we can gain new insights into how cancers initiate and how we might prevent them.