RT null
T1 Selective genome editing of amplified oncogenes triggers immunogenic cell death and tumor remodeling
A1 Nieto Sanchez, A.
A1 Roda Navarro, Pedro
A1 Rodríguez Perales, Sandra
AB Oncogene amplifications fuel some of the most lethal, therapy‑refractory cancers, yet remain clinically untargeted. We report a single‑guide CRISPR/Cas9 strategy that converts the sheer copy‑number excess of oncogene amplicons into an Achilles' heel. A solitary intronic double‑strand break is innocuous in diploid genomes but collapses oncogene amplification‑positive cells across neuroblastoma, small‑cell lung and colorectal carcinoma models, driving > 90% loss of viability, G₂/M blockade and catastrophic DNA‑damage signalling. Amplified‑locus cleavage rewires transcription toward cell death activation, necroptosis and cGAS-STING-mediated immunogenic cell death, enabling dendritic‑cell cross‑priming and T‑cell activation and proliferation. In xenografts, delivery of the intronic sgRNA shrinks tumours by 90%, prolongs survival and remodels the innate tumour microenvironment. Deep sequencing confirms negligible off‑target editing, and combination with doxorubicin achieves supra‑additive killing. These findings establish amplification density, not sequence content, as a tractable, tumour‑exclusive target and unveil a dual‑action platform that is simultaneously cytotoxic and immunostimulatory. Editing of tumor amplifications therefore offers a blueprint for translating copy‑number aberrations into precision genome‑editing therapies for treatment‑resistant cancers.
PB Springer Nature
SN 1476-4598
YR 2025
FD 2025-12-25
LK https://hdl.handle.net/20.500.14352/133954
UL https://hdl.handle.net/20.500.14352/133954
LA eng
NO Nieto-Sanchez A, Martinez-Lage M, Puig-Serra P, Carpintero S, Alonso-Yanez A, Ojeda-Walczuk P, Ibañez-Navarro M, Pita G, Moya FJ, Moreno C, Martin MC, Alonso R, Nuñez-Torres R, Sanchez-Arevalo Lobo VJ, Alonso-Guirado L, Malats N, Gonzalez-Neira A, Fernandez L, Roda-Navarro P, Torres-Ruiz R, Rodriguez-Perales S. Selective genome editing of amplified oncogenes triggers immunogenic cell death and tumor remodeling. Mol Cancer. 2025 Dec 22;25(1):21. doi: 10.1186/s12943-025-02542-0
NO Financiado con Fondos FEDER
NO Agencia Estatal de Investigación (España)
NO Instituto de Salud Carlos III (España)
DS Docta Complutense
RD 8 jun 2026