A study published in Nature shows that cellular states linked to metastasis already arise as soon as invasive colon cancers are formed, but are surprisingly not enough to cause spread by themselves. The findings may help to improve metastatic risk assessment and prevent unnecessary surgeries.

Approximately five years ago, research led by Oncode investigator Hugo Snippert at UMC Utrecht made a shift in focus towards prevention of metastatic disease. Inspired by clinical partners Leon Moons (UMC Utrecht, gastroenterologist) and Miangela Laclé (UMC Utrecht, pathologist), the team started to investigate the earliest stages of cancer development that had long been considered in accessible in patients, as they often go unnoticed.

Due to national colorectal cancer screening programmes, we have seen a remarkable shift towards detection of its earlier stages. Generally, the earliest stages are removed without invasive treatments and the patients are considered to be cured, as lethal metastases are usually a late event. In clinical practice, however, a small number of patients with very early cancers have already developed distant metastases. This observation raises a fundamental and long-standing question: when, where and how does a tumour gain the ability to spread?

At the same time, gaining basic insights into the underlying biology of so-called T1 cancers will help to address a critical clinical challenge. It remains difficult to identify which T1 tumour already possesses metastatic capacity. Consequently, many non-metastatic patients receive unnecessary additional surgery, with risk of morbidity and even a small percentage of mortality. Ultimately, improving metastatic risk assessment for early-stage colon cancer remains a matter of cardinal importance.

Organoid models of the first invasive step

A team effort of scientists from the Snippert lab developed strategies to experimentally analyse the so-called T1 colon cancers and determine when metastasis-related cell states first emerge. To examine how the ability to spread develops, the team created an organoid biobank of early-stage tumours. Specifically, they made multiple organoid models per tumor, each obtained from a successive region along the evolutionary timeline of that lesion. Organoids are ‘mini-organs’ grown in the lab and enabled the researchers to study cancer cells in real time, right under their microscope. Whole-genome sequencing and spatial gene expression analyses of the cancers provided real-world context and were used to study both tumour cells and their surrounding tissue.

Early changes at the invasive front

When examining the invasive front of tumour specimens, tumour cells consistently showed regenerative, fetal-like programmes known as oncofetal states. In advanced cancers, these programmes have been linked to metastatic relapse and therapy resistance. Surprisingly, these states were widely present among most early-stage tumours, including in many patients that never showed signs of metastases. Apparently, oncofetal cells are a prerequisite for metastatic spread as shown in multiple examples in the literature, but this is not enough to cause spread on its own.

Leon Moons, Clinical Scientist at UMC Utrecht and collaborator on the study, says:

The role of the surrounding tissue

Genetic analyses revealed no new mutations within the oncofetal cells. Instead, interactions with the surrounding tissue played a central role in controlling these early phenotypic changes. Specifically, the relative positioning of stromal cells and subtypes (patterning) within the normal tissue architecture of the gut turned out to be a strong determinant of the time and place at which oncofetal states are induced in tumour cells. In short: upon the start of invasive growth, the cancer enters the submucosa, an area that is densely populated by a specific population of fibroblasts named trophocytes. A close encounter between tumour cells and trophocytes instigates the latter to acquire features of early cancer-associated fibroblasts (CAFs), identifying them as the elusive cell of origin for the well-known CAFs from late-stage cancers. Subsequently, using functional co-culture experiments, the authors confirmed that early trophocyte-like CAFs in turn induce phenotypic plasticity in tumour cells to switch into oncofetal states through signals such as TGFβ and prostaglandins.

Prevention, rather than curing metastatic disease

Metastases are most often associated with advanced disease. This study shows that important changes underlying metastatic spread occur much earlier than anticipated, i.e. at the first moments after tumours become malignant. Paradoxically, most of these early cancers that display these changes never metastasize, highlighting that other barriers, including immune-related mechanisms, may control successful spread of tumour cells.

A basic understanding of the phenotypic changes in tumour and stroma that drive initial malignant transformation may help to identify markers that distinguish tumours that remain localised from those that will disseminate and become lethal. Improving this distinction could refine risk assessment in early-stage colon cancer, reducing unnecessary treatments while ensuring that high-risk patients are recognised in time. Snippert, whose laboratory relocated to the Princess Máxima Center for pediatric oncology in 2025, is embracing the challenge of broadening his focus again to understand how any type of cancer starts.