Multi-lineage reprogramming and NOTCH-associated signaling remodeling characterize the aggressive biology of early-onset colorectal cancer
Year: 2026
Type: article
Abstract: Introduction Early-onset colorectal cancer (EOCRC), defined as colorectal cancer diagnosed before 50 years of age, represents an emerging global health challenge with rapidly increasing incidence. Although EOCRC exhibits distinct clinical and molecular characteristics, the cellular ecosystem and mechanisms underlying its aggressive behavior remain incompletely understood. Methods Here, we integrated seven independent single-cell RNA sequencing cohorts comprising 473,939 high-quality cells from 174 colorectal cancer (CRC) patients (39 EOCRC and 135 average-onset CRC [AOCRC]) to construct a comprehensive cellular landscape across age groups. After Harmony-based integration, nine major cellular lineages were identified, and malignant epithelial cells were characterized using chromosome-level copy number variation inference. We systematically compared malignant and stromal compartments, followed by malignant-state characterization, trajectory analysis, and cell -cell communication modeling using Slingshot, CellChat, and NicheNet. Results EOCRC displayed extensive remodeling of the tumor ecosystem rather than isolated epithelial alterations. Malignant epithelial cells in EOCRC showed increased enrichment of inflammation-associated and Cycling (S/DNA damage response [DDR]) states. In parallel, proliferating endothelial cells and MKI67-positive proliferative cancer-associated fibroblasts were expanded in EOCRC, indicating stromal-state remodeling. Copy number variation analyses demonstrated that genomic instability differences between EOCRC and AOCRC were primarily explained by differential microsatellite instability (MSI) status distribution rather than age-related genomic alterations. Cell -cell communication analyses revealed selective remodeling of epithelial-stromal signaling networks, with recurrent involvement of NOTCH-associated mediators. NicheNet prioritized NOTCH-associated ligands (DLL4, JAG1) among candidate stromal-derived regulators of EOCRC transcriptional programs. A refined five-gene NOTCH-epithelial-mesenchymal transition (EMT) panel (HEY1, ZEB1, TWIST1, VIM, FN1) was associated with EOCRC-specific poor survival across two independent cohorts, and in silico perturbation further suggested that increased HEY1 activity may reinforce the proliferative state enriched in EOCRC. Discussion Together, our study establishes EOCRC as a multicellular ecosystem characterized by coordinated malignant, stromal, and signaling reprogramming. These findings identify NOTCH signaling as a potential age-specific prognostic association that warrants functional validation in EOCRC.
Source: Frontiers in Oncology
Authors: Hongda Shi, Li Qiao, Qianqian Su, Hui Gao, Yang Cao
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223177891