Summary
A single-nucleus atlas of colorectal tumours found a higher stromal-to-epithelial ratio in younger patients with microsatellite-stable cancer. The study also identified age-associated RNA signals and differences in computationally inferred cell communication.
A study published in Nature Medicine on 29 October 2026 mapped gene activity in 850,222 nuclei from 189 primary colorectal cancers, comparing tumours diagnosed before age 50 with those diagnosed at 50 or older. In microsatellite-stable (MSS) cancers, tumours from younger patients had a higher proportion of stromal cells relative to tumour epithelial cells. The researchers also found age-associated differences in gene expression and in cell-to-cell signalling estimated from the data.
The atlas offers a detailed view of the different cell populations within colorectal tumours. Its findings point to biological features that may help guide further research into early-onset colorectal cancer, but the study is observational and does not show that these features cause the disease or its clinical course.
A higher stromal-to-epithelial ratio in younger MSS tumours
The team used single-nucleus RNA sequencing, which measures gene activity in individual cell nuclei, to profile 54 early-onset colorectal cancers (diagnosed before age 50) and 135 average-onset cancers (diagnosed at age 50 or older). The samples spanned eight decades of life. Analyses accounted for factors including tumour sidedness, stage, sex and prior treatment, and modelled age continuously where possible.
Among MSS tumours, younger age was associated with a lower proportion of epithelial cells relative to other cell lineages, including stromal cells. The researchers checked this pattern in separate datasets: bulk RNA sequencing from 564 MSS tumours and multispectral immunofluorescence with machine learning in 712 MSS tumours. In the latter cohort, the stromal-to-epithelial ratio was inversely correlated with age at diagnosis (Spearman’s ρ = −0.11, P = 0.003). This confirms an age-associated pattern across cohorts, though the correlation was modest.
Stromal cells form part of the tissue surrounding and supporting a tumour. Their relative abundance can help describe the tumour’s local cellular environment; it is not, by itself, evidence that stromal cells cause cancer progression.
RNA signals and inferred cell communication
In MSS tumours, several genes—including the gene FN1 and multiple long noncoding RNAs—had higher expression in younger patients’ tumours. Long noncoding RNAs are RNA molecules that do not encode proteins; many of the age-associated examples identified here are not well characterised in colorectal cancer. Some of the gene-expression results also appeared in an independent bulk RNA-sequencing cohort.
For a smaller group of left-sided MSS tumours—25 early-onset and 26 average-onset—the researchers used CellChat to estimate communication between cell types from gene-expression patterns. The analysis identified more interactions in the early-onset group and stronger or unique signals in pathways including FN1, GDF and ACTIVIN. The authors interpreted these patterns as consistent with epithelial-to-mesenchymal transition and angiogenesis-related signalling. CellChat infers possible signalling from molecular data; it does not directly observe cells communicating in a living tumour.
The atlas also showed that many features were shared across age groups. The researchers did not find a significant age association with copy-number alteration burden in MSS tumours, although they observed a borderline trend toward greater copy-number heterogeneity in younger patients’ tumours. The authors describe the results as hypothesis-generating: functional studies will be needed to determine whether the observed cellular and molecular patterns contribute to early-onset disease or could inform prevention or treatment.