Identification of tumor initiating cells and early marker genes in histologically normal colonic mucosa that lead to neoplastic transformation

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BACKGROUND & AIMS: Colorectal cancer (CRC) remains a leading cause of cancer‑related morbidity and mortality worldwide. Although the adenoma-carcinoma sequence and its genetic drivers are well described, the earliest cellular and molecular events initiating tumorigenesis within histologically normal colonic epithelium remain poorly defined. This study aims to identify tumor‑initiating cells (TICs), distinguish them from normal stem‑like cells (nSTMs), and delineate early transcriptional and signaling programs using single‑cell RNA sequencing (scRNA‑seq) from paired normal‑appearing and transformed human colonic tissues. METHODS: Fresh biopsies from histologically normal mucosa and matched polyps, including tubular adenomas, sessile serrated adenomas, and adenocarcinomas, were collected from seven subjects. Single‑cell transcriptomes were generated using the 10x Genomics platform and analyzed with Seurat, Monocle2, CytoTRACE, GSEA/GSVA, RNA velocity, InferCNV, CellChat, and NicheNet. Spatial validation was performed using RNA‑FISH. RESULTS: We resolved 51,054 high‑quality single‑cell transcriptomes into 33 clusters. Tumor-specific stem-like (tSTM) and deep crypt secretory (tDCS) populations were enriched in adenomas. Subclustering of tSTM identified TIC-like subsets predominantly derived from histologically normal mucosa that localized to the root of lineage trajectories leading to polyp-enriched tSTM states. Compared to nSTMs, TICs exhibited enhanced stemness potential, early epithelial-mesenchymal transition (EMT) and interferon signaling, suppression of oxidative phosphorylation, and distinct genomic and signaling features, indicating early neoplastic reprogramming. ETS2, SLC12A2, and LEFTY1 were identified as TIC‑specific markers; SOD3 and GPRC5A increased along the TIC‑to‑tSTM trajectory. RNA‑FISH confirmed candidate marker localization. Independent validation using the COLONMAP dataset (30 polyps, 35 normal samples) demonstrated that TIC-like cells were predominantly enriched in tubular adenomas but were scarce in serrated lesions. Across this independent cohort, TIC marker genes showed reproducible upregulation in TIC-like populations, supporting the robustness of these observations across cohorts. CONCLUSIONS: Our results identify TICs as the origin of neoplastic stem‑like states in the conventional tubular adenoma pathway and define early transcriptional, metabolic, and microenvironmental reprogramming events that distinguish TICs from nSTMs. In contrast to serrated pathways described in other atlases, our data support a stem‑like expansion model for tubular adenomas and nominate biomarkers with translational potential for early CRC detection and intervention.

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