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Neuro-Immune Crypt-Associated Cells And Rest-Mediated Reprogramming: Pathogen-Driven Stromal Activation, Hervs Induction, And Abortive Antiviral Signaling In Colorectal Carcinoma

Diaz-Carballo, D.; Noa Bolano, A.; Udo Rahner, U.; Acikelli, A. H.; Saka, S.; Klein, J.; DSouza, F.; Sascha Malak, S.; Anne Hoeppner, A.; Kamitz, A.; Casula, C.; Kamada, L.; Tannapfel, A.; Christmann, J.; Albus, S.; Fruth, E.; Gerovska, D.; Arauzo-Bravo, M. J.; Senkal, M.; Ochsenfarth, C.; Berres, S.; Uszkoreit, J.; Strumberg, D.

2026-03-02 cancer biology
10.1101/2025.10.21.682573 bioRxiv
Show abstract

Colorectal cancer (CRC) pathogenesis remains linked to poorly defined cellular origins and microenvironmental drivers. We identify Neuro-Immune Crypt-Associated (NICA) cells as a privileged pathogen portal and a plausible epithelial cell of origin. During carcinogenesis, the repressor REST drives a neuroendocrine-to-epithelial transition by silencing NICA-associated neuroendocrine markers, a lineage loss reversible via epigenetic modulation or genetic ablation in CRC models. This landscape is further shaped by EBV-infected B-lineage cells (BLEICS), which transactivate HERV-H/F elements in CRC cells through paracrine signaling, establishing a niche-restricted viral scar. While tumor crypts sense this retroviral pressure, they exhibit an abortive antiviral signature marked by RNase L downregulation, creating a functional execution gap. We propose a pathogen-first model where chronic inflammatory pressure triggers mutation-silencing -the simultaneous genotoxic and epigenetic inactivation of tumor suppressors. Together, the convergence of NICA plasticity, BLEICS-mediated HERV induction, and compromised antiviral surveillance redefines CRC as a pathogen-driven disruption of the neuro-immune niche.

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