Neuro-Immune Crypt-Associated Cells Drive Colorectal Carcinogenesis via REST-Mediated Phenotypic Reprogramming: Implications for Tumorigenesis and Viral Susceptibility

Colorectal cancer (CRC) incidence correlates anatomically with a shared gradient of lymphoid follicles and previously defined neuroendocrine cells. We now define the cellular basis for this observation by identifying a resident cell in the colonic crypts, the Neuro-Immune Crypt-Associated (NICA) cell, characterized by a unique triple phenotype: neuronal (ChgA, TH, peripherin, somatostatin, NSE), robust stemness markers (LGR5, CD133, Glut3, ASCL2, β-catenin), and a diverse array of innate immune molecules (TLR4, CD80, SDF-1). These markers (excluding ChgA) are retained in malignant CRC sections, demonstrating lineage persistence. Functioning as a pathogen gateway, NICA cells express viral entry receptors and the CXCR4 ligand SDF-1, rendering them susceptible to Epstein-Barr Virus (EBV) infection and subsequent immune cell recruitment. Crucially, we define a novel oncogenic intermediate: the BLEICS (B-Lymphocyte, EBV-Infected, Calamari-Shaped) cell, which exhibits a B cell-myeloid hybrid signature and high CXCR4. The fusion between BLEICS and crypt cells, facilitated by fusogenic Human Endogenous Retrovirus (HERV) envelope proteins, generates the malignant, hybrid CRC lineage. Furthermore, BLEICS cells actively engage cancer-associated fibroblasts (CAFs) via the CXCR4-SDF-1 axis to drive stromal expansion and crypt enlargement. In the resulting CRC cells, the overexpression of the transcription factor REST actively suppresses the neuronal identity (e.g., TH, ChgA), thereby maintaining the proliferative stemness phenotype (LGR5). The specific loss of ChgA in CRC is attributable to REST activity. We show that REST ablation restores ChgA expression and reinstates neuronal differentiation and induces growth arrest, an effect mirrored by pharmacological REST inhibition using valproic acid. This study establishes a new pathogenesis model where the increasing density of lymphoid follicles and NICA precursor cells toward the rectum creates an ideal niche for viral-driven, immune-cell fusion, providing mechanistic targets for REST-driven differentiation therapy and EBV vaccination strategies.