Early-Onset Colorectal Cancer Tumors Show Distinct Cellular Composition
A new single-nucleus RNA sequencing atlas reveals that colorectal cancers in younger patients have a higher proportion of stromal cells and lower proportion of epithelial cells compared to tumors in older individuals. This fundamental difference in the tumor microenvironment, validated across large external cohorts, is linked to specific molecular subtypes and signaling pathways.
Tumors from younger patients with early-onset colorectal cancer exhibit significantly higher stromal and lower epithelial proportions compared to average-onset cases. This compositional shift, confirmed across multiple large external cohorts, points to a distinct biological basis for cancers rising in younger adults.
Among microsatellite-stable tumors, those from younger patients were characterized by increased stromal and decreased epithelial proportions. Researchers validated this stromal enrichment in 712 tumors using multispectral immunofluorescence and machine learning. Cell type deconvolution in 493 samples revealed a significant decrease in the stromal-to-epithelial cell ratio with age.
Molecular profiles differ by age and subtype
A single-nucleus RNA sequencing atlas was generated from 189 primary colorectal cancer tumors spanning eight decades of life, with at least 20 tumors in most age decades. The incidence of early-onset colorectal cancer, diagnosed before age 50, is increasing worldwide at a rate of 1-3% per year since the mid-1990s.
Early-onset tumors were more likely to be classified as CMS2 and less likely to be CMS1. CMS1 remained significantly less likely in tumors from young patients after statistical adjustment. Tumor epithelial cells from young patients exhibited increased expression of long noncoding RNAs and the FN1 gene. There is also a trend toward greater intratumoral heterogeneity in these tumors.
The atlas provides a detailed cellular census:
| Cell Lineage | Proportion of Cells |
|---|---|
| Epithelial | 84.9% |
| Stromal | 5.6% |
| Myeloid | 3.1% |
| Endothelial | 2.7% |
| T cells | 2.5% |
| B cells | 1.1% |
| Glial/Neuronal | 0.1% |
Cell-type interactions and signaling pathways
Microsatellite-stable, left-sided early-onset tumors displayed more cell-cell interactions. Epithelial-to-mesenchymal transition-related signaling pathways, including FN1, GDF, and ACTIVIN, showed increased, cell type-specific activity. Inferred interactions suggest enhanced tumor-stroma crosstalk in younger patients.
Thirteen distinct stromal cell subsets were identified, including various fibroblasts, pericytes, and adipocytes. The study also annotated ten T-cell subsets, six B-cell subsets, and three glial/neuronal subsets. Among granular epithelial subsets, several increased in proportion with age in microsatellite-stable tumors. Stromal remodeling and epithelial-to-mesenchymal transition-associated signaling emerge as potential therapeutic vulnerabilities.
Implications for screening and biology
The rising incidence of early-onset disease and the identified molecular shifts may influence future screening guidelines and therapeutic targeting. In response to the trend, both the American Cancer Society and the US Preventive Services Task Force have taken action. The American Cancer Society said: "lowered the recommended CRC screening age from 50 to 45 years for average-risk individuals."
Further investigation is needed to determine whether the identified stromal and epithelial-to-mesenchymal transition-associated signaling pathways can be exploited for new therapeutics for early-onset disease.
